Articles de revues : « Tumour Tropism »

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Lee, Soo Youn, Jung Mi Kim, Soo Young Cho, Hyun Suk Kim, Hee Sun Shin, Jeong Yong Jeon, Rukhsana Kausar, Seon Yong Jeong, Young Seek Lee et Myung Ae Lee. « TIMP-1 modulates chemotaxis of human neural stem cells through CD63 and integrin signalling ». Biochemical Journal 459, n^o 3 (11 avril 2014) : 565–76. http://dx.doi.org/10.1042/bj20131119.

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Human neural stem cells possess an inherent brain tumour tropism. We identified brain tumour-derived TIMP-1 as a novel chemoattractant for human neural stem cells. TIMP-1 binding to CD63 at the plasma membrane activated β1 integrin-mediated signalling, inducing cell adhesion and migration.

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Frizziero, M., A. Malik, M. G. McNamara, S. Jamdar, R. Pihlak, A. Siriwardena, D. O'Reilly, N. De' Liguori Carino et A. Lamarca. « Resected pancreatic ductal adenocarcinoma : understanding tumour tropism to maximise benefit from surgery ». HPB 23 (2021) : S228—S229. http://dx.doi.org/10.1016/j.hpb.2020.11.573.

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Shaik Fakiruddin, Kamal, Nadiah Ghazalli, Moon Lim, Zubaidah Zakaria et Syahril Abdullah. « Mesenchymal Stem Cell Expressing TRAIL as Targeted Therapy against Sensitised Tumour ». International Journal of Molecular Sciences 19, n^o 8 (27 juillet 2018) : 2188. http://dx.doi.org/10.3390/ijms19082188.

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Tapping into the ability of engineered mesenchymal stem cells (MSCs) to mobilise into the tumour has expanded the scope of cancer treatment. Engineered MSCs expressing tumour necrosis factor (TNF)-related apoptosis inducing ligand (MSC-TRAIL) could serve as a platform for an efficient and targeted form of therapy. However, the presence of cancer stem cells (CSCs) that are resistant to TRAIL and apoptosis may represent a challenge for effective treatment. Nonetheless, with the discovery of small molecular inhibitors that could target CSCs and tumour signalling pathways, a higher efficacy of MSC-TRAIL mediated tumour inhibition can be achieved. This might pave the way for a more effective form of combined therapy, which leads to a better treatment outcome. In this review, we first discuss the tumour-homing capacity of MSCs, its effect in tumour tropism, the different approach behind genetically-engineered MSCs, and the efficacy and safety of each agent delivered by these MSCs. Then, we focus on how sensitisation of CSCs and tumours using small molecular inhibitors can increase the effect of these cells to either TRAIL or MSC-TRAIL mediated inhibition. In the conclusion, we address a few questions and safety concerns regarding the utilization of engineered MSCs for future treatment in patients.

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Cheng, Yan, Liru Li, Dejun Wang, Qiuyan Guo, Yanan He, Tian Liang, Liyuan Sun, Xiaojun Wang, Yulei Cheng et Guangmei Zhang. « Characteristics of Human Endometrium-Derived Mesenchymal Stem Cells and Their Tropism to Endometriosis ». Stem Cells International 2017 (2017) : 1–9. http://dx.doi.org/10.1155/2017/4794827.

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Human endometrial tissue has become an attractive source of mesenchymal stem cells (MSCs) for cell-based therapies because these MSCs can be easily harvested and have tumour tropism as well as reduced immunogenic and inflammatory properties. Our study aimed to obtain and characterise human endometrial mesenchymal stem cells (EMSCs) and assess their endometriosis tropism. EMSCs were successfully isolated from the endometrium of women undergoing laparoscopy for idiopathic infertility. The EMSCs presented a fibroblast-like morphology during culture. Flow cytometry analyses showed that the cells were positive for the specific stem cell markers CD73, CD90, CD105, CD166, and HLA-ABC (major histocompatibility complex class I (MHC I)) but negative for CD14, CD34, CD45, and HLA-DR (MHC II). Reverse transcription polymerase chain reaction results showed that the EMSCs expressed the stem cell marker OCT4. The EMSCs could differentiate into osteocytes, adipocytes, and chondrocytes under certain conditions. The EMSCs had a high tropism to endometriosis without tumourigenicity. This study enhances the possibility of using EMSCs as drug carriers in human cell-based therapies. Meanwhile, future research could also focus on developing targeted therapies for endometriosis.

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Collins, Emma C., et Terence H. Rabbitts. « The promiscuous MLL gene links chromosomal translocations to cellular differentiation and tumour tropism ». Trends in Molecular Medicine 8, n^o 9 (septembre 2002) : 436–42. http://dx.doi.org/10.1016/s1471-4914(02)02397-3.

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Yanagi, Yusuke, Makoto Takeda et Shinji Ohno. « Measles virus : cellular receptors, tropism and pathogenesis ». Journal of General Virology 87, n^o 10 (1 octobre 2006) : 2767–79. http://dx.doi.org/10.1099/vir.0.82221-0.

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Measles virus (MV), a member of the genus Morbillivirus in the family Paramyxoviridae, is an enveloped virus with a non-segmented, negative-strand RNA genome. It has two envelope glycoproteins, the haemagglutinin (H) and fusion proteins, which are responsible for attachment and membrane fusion, respectively. Human signalling lymphocyte activation molecule (SLAM; also called CD150), a membrane glycoprotein of the immunoglobulin superfamily, acts as a cellular receptor for MV. SLAM is expressed on immature thymocytes, activated lymphocytes, macrophages and dendritic cells and regulates production of interleukin (IL)-4 and IL-13 by CD4+ T cells, as well as production of IL-12, tumour necrosis factor alpha and nitric oxide by macrophages. The distribution of SLAM is in accord with the lymphotropism and immunosuppressive nature of MV. Canine distemper virus and Rinderpest virus, other members of the genus Morbillivirus, also use canine and bovine SLAM as receptors, respectively. Laboratory-adapted MV strains may use the ubiquitously expressed CD46, a complement-regulatory molecule, as an alternative receptor through amino acid substitutions in the H protein. Furthermore, MV can infect SLAM− cells, albeit inefficiently, via the SLAM- and CD46-independent pathway, which may account for MV infection of epithelial, endothelial and neuronal cells in vivo. MV infection, however, is not determined entirely by the H protein–receptor interaction, and other MV proteins can also contribute to its efficient growth by facilitating virus replication at post-entry steps. Identification of SLAM as the principal receptor for MV has provided us with an important clue for better understanding of MV tropism and pathogenesis.

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Ohyashiki, Junko H., Tomohiro Umezu et Kazuma Ohyashiki. « Extracellular vesicle-mediated cell–cell communication in haematological neoplasms ». Philosophical Transactions of the Royal Society B : Biological Sciences 373, n^o 1737 (20 novembre 2017) : 20160484. http://dx.doi.org/10.1098/rstb.2016.0484.

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Crosstalk between bone marrow tumour cells and surrounding cells, including bone marrow mesenchymal stromal cells (BM-MSCs), endothelial cells and immune cells, is important for tumour growth in haematological neoplasms. In addition to conventional signalling pathways, extracellular vesicles (EVs), which are endosome-derived vesicles containing proteins, mRNAs, lipids and miRNAs, can facilitate modulation of the bone marrow microenvironment without directly contacting non-tumourous cells. In this review, we discuss the current understanding of EV-mediated cell–cell communication in haematological neoplasms, particularly leukaemia and multiple myeloma. We highlight the actions of tumour and BM-MSC EVs in multiple myeloma. The origin of EVs, their tropism and mechanism of EV transfer are emerging issues that need to be addressed in EV-mediated cell–cell communication in haematological neoplasms. This article is part of the discussion meeting issue ‘Extracellular vesicles and the tumour microenvironment’.

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Innao, Vanessa, Vincenzo Rizzo, Andrea Gaetano Allegra, Caterina Musolino et Alessandro Allegra. « Oncolytic Viruses and Hematological Malignancies : A New Class of Immunotherapy Drugs ». Current Oncology 28, n^o 1 (25 décembre 2020) : 159–83. http://dx.doi.org/10.3390/curroncol28010019.

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The use of viruses for tumour treatment has been imagined more than one hundred years ago, when it was reported that viral diseases were occasionally leading to a decrease in neoplastic lesions. Oncolytic viruses (OVs) seem to have a specific tropism for tumour cells. Previously, it was hypothesised that OVs’ antineoplastic actions were mainly due to their ability to contaminate, proliferate and destroy tumour cells and the immediate destructive effect on cells was believed to be the single mechanism of action of OVs’ action. Instead, it has been established that oncolytic viruses operate via a multiplicity of systems, including mutation of tumour milieu and a composite change of the activity of immune effectors. Oncolytic viruses redesign the tumour environment towards an antitumour milieu. The aim of our work is to evaluate the findings present in the literature about the use of OVs in the cure of haematological neoplastic pathologies such as multiple myeloma, acute and chronic myeloid leukaemia, and lymphoproliferative diseases. Further experimentations are essential to recognize the most efficient virus or treatment combinations for specific haematological diseases, and the combinations able to induce the strongest immune response.

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STUBENRAUCH, Kay, Stefan GLEITER, Ulrich BRINKMANN, Rainer RUDOLPH et Hauke LILIE. « Conjugation of an antibody Fv fragment to a virus coat protein : cell-specific targeting of recombinant polyoma-virus-like particles ». Biochemical Journal 356, n^o 3 (8 juin 2001) : 867–73. http://dx.doi.org/10.1042/bj3560867.

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The development of cell-type-specific delivery systems is highly desirable for gene-therapeutic applications. Current virus-based vector systems show broad cell specificity, which results in the need to restrict the natural tropism of these viral systems. Here we demonstrate that tumour-cell-specific virus-like particles can be functionally assembled in vitro from recombinant viral coat protein expressed in Escherichia coli. The insertion of a negatively charged peptide in the HI loop of polyoma VP1 interferes with the binding of VP1 to the natural recognition site on mammalian cells and also serves as an adapter for the coupling of antibody fragments that contain complementary charged fusion peptides. A recombinant antibody fragment of the tumour-specific anti-(Lewis Y) antibody B3 could be coupled to the mutant VP1 by engineered polyionic peptides and an additional disulphide bond. With this system an entirely recombinant cell-specific delivery system assembled in vitro could be generated that transfers genes preferentially to cells presenting the tumour-specific antigen on the cell surface.

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Parkins, Katie M., Amanda M. Hamilton, Veronica P. Dubois, Suzanne M. Wong, Paula J. Foster et John A. Ronald. « Cellular MRI Reveals Altered Brain Arrest of Genetically Engineered Metastatic Breast Cancer Cells ». Contrast Media & ; Molecular Imaging 2019 (8 janvier 2019) : 1–7. http://dx.doi.org/10.1155/2019/6501231.

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Purpose. The combined use of anatomical magnetic resonance imaging (MRI), cellular MRI, and bioluminescence imaging (BLI) allows for sensitive and improved monitoring of brain metastasis in preclinical cancer models. By using these complementary technologies, we can acquire measurements of viable single cell arrest in the brain after systemic administration, the clearance and/or retention of these cells thereafter, the growth into overt tumours, and quantification of tumour volume and relative cancer cell viability over time. While BLI is very useful in measuring cell viability, some considerations have been reported using cells engineered with luciferase such as increased tumour volume variation, changes in pattern of metastatic disease, and inhibition of in vivo tumour growth. Procedures. Here, we apply cellular and anatomical MRI to evaluate in vivo growth differences between iron oxide labeled naïve (4T1BR5) and luciferase-expressing (4T1BR5-FLuc-GFP) murine brain-seeking breast cancer cells. Balb/C mice received an intracardiac injection of 20,000 cells and were imaged with MRI on days 0 and 14. Mice that received 4T1BR5-FLuc-GFP cells were also imaged with BLI on days 0 and 14. Results. The number of signal voids in the brain (representing iron-labeled cancer cells) on day 0 was significantly higher in mice receiving 4T1BR5 cells compared to mice receiving 4T1BR5-FLuc-GFP cells (p<0.0001). Mice that received 4T1BR5 cells also had significantly higher total brain tumour burden and number of brain metastases than mice that received 4T1BR5-FLuc-GFP cells (p<0.0001). Conclusions. By employing highly sensitive cellular MRI tools, we demonstrate that engineered cells did not form tumours as well as their naïve counterparts, which appear to primarily be due to a reduction in cell arrest. These results indicate that engineering cancer cells with reporter genes may alter their tropism towards particular organs and highlight another important consideration for research groups that use reporter gene imaging to track metastatic cancer cell fate in vivo.

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Gao, Hua-Xin, Shawn Anderson, Lingjing Chen, Cigall Kadoch, Byron C. Hann, Clifford Lowell, Colin Collins et James L. Rubenstein. « Genomic and Molecular Properties of Relapsed CNS Lymphoma Using Novel Primary Meningeal Lymphoma Cell Lines and Intracranial Xenografts »,. Blood 118, n^o 21 (18 novembre 2011) : 3477. http://dx.doi.org/10.1182/blood.v118.21.3477.3477.

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Abstract Abstract 3477 Background: There is a paucity of molecular information regarding the phenotype of relapsed aggressive CNS lymphoma, a condition for which there are few effective treatment options and, as a consequence, patient survival is often short. To test our hypothesis that the molecular properties of CNS lymphoma at relapse are distinct from those at diagnosis we pursued two parallel lines of investigation: 1) the genomic analysis of relapsed aggressive CNS lymphomas in comparison to newly diagnosed specimens and 2) the generation of novel CNS lymphoma cell lines derived from recurrent meningeal lymphomas isolated from the cerebrospinal fluid. We hypothesize that this approach will facilitate the identification of the underlying molecular determinants of tumour progression, novel genome-based biomarkers and therapeutic targets. Methods: We compared genome copy number using high-resolution array comparative genomic hybridization (array-CGH) and used bioinformatics to study a carefully selected cohort of tumours comprised of 10 newly-diagnosed primary CNS lymphomas (large B-cell) and 7 relapsed/refractory CNS lymphomas (5 large B-cell, 2 of transformed histology). We evaluated copy number aberrations that occurred in the tumour cohort as a whole as well as those that occur predominantly in relapsed cases. In addition, we established five novel lymphoma cell lines from relapsed cases, three of which were derived from meningeal lymphomas isolated from the cerebrospinal fluid and expanded upon intracranial implantation in NSG mice as patient-derived xenografts. Results: There was a trend for an increase in the proportion of copy number losses involving the short arm of chromosome 6 as well as overall gains on chromosome 12 among the relapsed cases. Significant DNA copy number gains for STAT6 were noted in 4/7 relapsed cases. We observed a significant number of deletions present in between 50–90% of newly diagnosed tumors that were absent in CNS lymphomas at relapse, suggestive of complex genomic remodeling during tumour evolution. In addition, a region with potential prognostic implications was identified at chromosome 19p.13.3 that was deleted in 57% of relapsed tumors but not in newly diagnosed cases. Three of the five relapsed large cell cases exhibited significant deletions, including one focal homozygous deletion, at chromosome 4q23.3–4q23.5, a region not previously shown to be deleted in large cell lymphoma (Lenz et al., PNAS, 2008). Both chromosomes 14 and 22 have copy number aberrations that occur in > 80% of all tumours as well as high frequency focal aberrations that appear linked to either good or poor prognosis. Significantly, the MTAP and CDKN2A genes at 9q21 are homozygously co-deleted in 18% of poor prognosis or relapsed patients. Notably, each of the orthotopic xenografts exhibited an ABC immunophenotype and were diffusely infiltrative with meningeal tropism. In fact, CNS metastasis to the meninges was recapitulated when the lymphoma cells were implanted in flank and spontaneously metastasized to brain, within three months post injection. In vitro chemotaxis assays demonstrated responsiveness of human meningeal lymphoma cells to CXCL-13 and SDF-1, chemokines postulated to contribute to the CNS tropism of NHL. Importantly, genomic aberrations identified in the parent tumours were retained when the relapsed meningeal lymphomas were serially passaged by intracranial implantation as xenografts, as evidenced by array-CGH. Conclusions: We believe that this study represents the first analysis of the biologic and genetic properties of relapsed CNS lymphoma. This analysis provides the first direct evidence that chemokines previously shown to be expressed in the CNS lymphoma microenvironment direct chemotaxis of meningeal lymphoma cells isolated from patients. This result is suggestive of a molecular mechanism which may be essential to CNS tropism. In addition, we have established the first in vivo model system of CNS lymphoma which retains the genomic properties of relapsed, refractory disease and which has significant potential for preclinical testing of novel therapeutic strategies. Supported by Leukemia and Lymphoma Society and NIH Grant CA13908301. Disclosures: No relevant conflicts of interest to declare.

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Poirier, John T., P. Seshidhar Reddy, Neeraja Idamakanti, Shawn S. Li, Kristine L. Stump, Kevin D. Burroughs, Paul L. Hallenbeck et Charles M. Rudin. « Characterization of a full-length infectious cDNA clone and a GFP reporter derivative of the oncolytic picornavirus SVV-001 ». Journal of General Virology 93, n^o 12 (1 décembre 2012) : 2606–13. http://dx.doi.org/10.1099/vir.0.046011-0.

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Seneca Valley virus (SVV-001) is an oncolytic picornavirus with selective tropism for a subset of human cancers with neuroendocrine differentiation. To characterize further the specificity of SVV-001 and its patterns and kinetics of intratumoral spread, bacterial plasmids encoding a cDNA clone of the full-length wild-type virus and a derivative virus expressing GFP were generated. The full-length cDNA of the SVV-001 RNA genome was cloned into a bacterial plasmid under the control of the T7 core promoter sequence to create an infectious cDNA clone, pNTX-09. A GFP reporter virus cDNA clone, pNTX-11, was then generated by cloning a fusion protein of GFP and the 2A protein from foot-and-mouth disease virus immediately following the native SVV-001 2A sequence. Recombinant GFP-expressing reporter virus, SVV–GFP, was rescued from cells transfected with in vitro RNA transcripts from pNTX-11 and propagated in cell culture. The proliferation kinetics of SVV-001 and SVV–GFP were indistinguishable. The SVV–GFP reporter virus was used to determine that a subpopulation of permissive cells is present in small-cell lung cancer cell lines previously thought to lack permissivity to SVV-001. Finally, it was shown that SVV–GFP administered to tumour-bearing animals homes in to and infects tumours whilst having no detectable tropism for normal mouse tissues at 1×1011 viral particles kg−1, a dose equivalent to that administered in ongoing clinical trials. These infectious clones will be of substantial value in further characterizing the biology of this virus and as a backbone for the generation of additional oncolytic derivatives.

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Seymour, LW, K. Ulbrich, PS Steyger, M. Brereton, V. Subr, J. Strohalm et R. Duncan. « Tumour tropism and anti-cancer efficacy of polymer-based doxorubicin prodrugs in the treatment of subcutaneous murine B16F10 melanoma ». British Journal of Cancer 70, n^o 4 (octobre 1994) : 636–41. http://dx.doi.org/10.1038/bjc.1994.363.

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Ponzetti, Marco, et Nadia Rucci. « Switching Homes : How Cancer Moves to Bone ». International Journal of Molecular Sciences 21, n^o 11 (9 juin 2020) : 4124. http://dx.doi.org/10.3390/ijms21114124.

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Bone metastases (BM) are a very common complication of the most prevalent human cancers. BM are extremely painful and may be life-threatening when associated with hypercalcaemia. BM can lead to kidney failure and cardiac arrhythmias and arrest, but why and how do cancer cells decide to “switch homes” and move to bone? In this review, we will present what answers science has provided so far, with focus on the molecular mechanisms and cellular aspects of well-established findings, such as the concept of “vicious cycle” and “osteolytic” vs. “osteosclerotic” bone metastases; as well as on novel concepts, such as cellular dormancy and extracellular vesicles. At the molecular level, we will focus on hypoxia-associated factors and angiogenesis, the Wnt pathway, parathyroid hormone-related peptide (PTHrP) and chemokines. At the supramolecular/cellular level, we will discuss tumour dormancy, id est the mechanisms through which a small contingent of tumour cells coming from the primary site may be kept dormant in the endosteal niche for many years. Finally, we will present a potential role for the multimolecular mediators known as extracellular vesicles in determining bone-tropism and establishing a premetastatic niche by influencing the bone microenvironment.

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Delgui, Laura, Dolores González et José F. Rodríguez. « Infectious bursal disease virus persistently infects bursal B-lymphoid DT40 cells ». Journal of General Virology 90, n^o 5 (1 mai 2009) : 1148–52. http://dx.doi.org/10.1099/vir.0.008870-0.

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Infectious bursal disease virus (IBDV), an important avian pathogen, exhibits a specific tropism for immature B-lymphocyte populations. We have investigated the ability of IBDV to replicate in chicken B-lymphoid DT40 cells, a tumour cell line derived from the bursa of Fabricius of a chicken infected with avian leukosis virus. Our results show that IBDV persistently infects DT40 cells. Establishment of the persistent infection is associated with an extensive remodelling of the hypervariable region of the VP2 capsid polypeptide, accumulating 14 amino acid changes during the first 60 days of the persistent infection. The amino acid sequence of the non-structural VP5 polypeptide, involved in virus dissemination, is not altered during the persistent infection. Results described in this report constitute the first demonstration of the ability of IBDV to establish a persistent infection in vitro.

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Ana Sami. « Next Generation Stem Cells and their Implications in Cancer Therapy ». Journal of the Pakistan Medical Association 73, n^o 2 (25 janvier 2023) : S98—S104. http://dx.doi.org/10.47391/jpma.akus-16.

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Stem cells have been implicated for decades in the treatment of hematological malignancies. These cells when isolated from the bone marrow, adipose tissue, or foetal tissue are deemed as the first generation of stem cells. The turn of the century saw the discovery of the second generation of stem cells such as the human Embryonic Stem Cells (hESCs) and induced Pluripotent Stem Cells (iPSCs). Advances in gene editing technology, in the past decade, have stimulated the rise of next-generation stem cells. Recent studies exploit the tumour tropism, multi-lineage differentiation, and auto-renewal capability of stem cells, and combine it with molecular biology techniques, to create potent anti-cancer therapies. Stem cells have been modified to have low immunogenicity and are thus being used as ‘trojan horses’ for the targeted, intra-tumoral delivery of anti-cancer drugs. continued...

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Tombal, Bertrand, et Frederic Lecouvet. « Modern Detection of Prostate Cancer's Bone Metastasis : Is the Bone Scan Era Over ? » Advances in Urology 2012 (2012) : 1–8. http://dx.doi.org/10.1155/2012/893193.

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Prostate cancer cells have an exquisite tropism for bone, which clinically translates into the highest rate of bone metastases amongst male cancers. Although in the latest years there has been an active development of new “bone targeted” therapies, modern diagnostic techniques for bone metastases still relies mostly on bone scanning (BS) and plain X-ray. BS dramatically lacks specificity and sensitivity. Recent publications using modern imaging technologies have clearly pinpointed that BS grossly underestimates the true prevalence of bone metastasis. In addition BS does not allow tumour measurement and is, therefore, not appropriate to monitor response to therapy. This might be extremely important in patients harbouring high-risk localized disease that are eventually candidate for local therapy. Here we reviewed what are the emerging imaging strategies that are likely to supplant BS and to what extent they can be used in the clinic already.

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Bayo-Puxan, Neus, Manel Cascallo, Alena Gros, Meritxell Huch, Cristina Fillat et Ramon Alemany. « Role of the putative heparan sulfate glycosaminoglycan-binding site of the adenovirus type 5 fiber shaft on liver detargeting and knob-mediated retargeting ». Journal of General Virology 87, n^o 9 (1 septembre 2006) : 2487–95. http://dx.doi.org/10.1099/vir.0.81889-0.

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Liver tropism hampers systemic administration of adenovirus in gene therapy and virotherapy. In consequence, tumour targeting requires the combination of capsid modifications that abrogate liver transduction and redirect adenoviral vectors to tumour cells. Coxsackievirus and adenovirus receptor (CAR), integrins and heparan sulfate glycosaminoglycans (HSG) are receptors involved in adenovirus type 5 (Ad5) entry into cells. The in vitro and in vivo properties of Ad5 vectors unable to bind CAR, integrins and HSG with and without Arg–Gly–Asp (RGD) inserted at the HI loop of the fiber were studied. As was previously observed with CAR-ablated vectors, CAR and integrin double binding-ablated vectors transduced hepatocytes less efficiently in vitro but not in vivo. On the contrary, the role of HSG on Ad5 infectivity was evident in vitro only when CAR binding was abrogated, but the shaft mutation that ablated HSG binding on the background of a normal capsid was sufficient to abrogate liver transduction in vivo. The insertion of amino acids RGD at the HI loop in a shaft-mutated fiber only partially rescued integrin-mediated infectivity. These results indicate that the shaft mutation precluded HSG binding and affected the structure of the fiber. The insertion of ligands at the hexon or protein IX may be required to benefit from the fiber shaft mutation-detargeting properties.

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Yi, B. R., K. A. Hwang et K. C. Choi. « 205 SELECTIVE ANTITUMOR THERAPEUTIC EFFECT OF 5-FLUOROCYTOSINE AND INTERFERON-BETA AGAINST BREAST AND ENDOMETRIAL CANCER CELLS BY ENGINEERED STEM CELLS EXPRESSING CYTOSINE DEAMINASE AND HUMAN INTERFERON-BETA ». Reproduction, Fertility and Development 24, n^o 1 (2012) : 215. http://dx.doi.org/10.1071/rdv24n1ab205.

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When genetically engineered with chemo- or immunotherapeutic genes, stem cells can exhibit a potent therapeutic efficacy combined with their strong tumour tropism. The stem cells were genetically engineered to express a bacterial cytosine deaminase (CD) gene and/or a human interferon-β (IFN-b) gene; thus, 2 stem cell lines, HB1.F3.CD and HB1.F3.CD.IFN-b, were generated, respectively. The CD gene, one of suicide gene, can convert the nontoxic prodrug 5-fluorocytosine (5-FC) to an active form, 5-fluorouracil (5-FU), which has a powerful cytotoxic effect on cancer cells. In addition, human IFN-b is a typical cytokine having an antitumour effect. Using reverse transcription-PCR (RT-PCR), we confirmed CD and/or IFN-b gene expression in HB1.F3 (maternal stem cells) and HB1.F3.CD and HB1.F3.CD.IFN-b cells and the expression of chemoattractant ligands and receptors including stem cell factor (SCF), CXCR4, c-kit, vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2) in breast (MCF-7) and endometrial cancer (Ishikawa) cells. To determine the migratory capability of engineered stem cells, we performed a modified trans-well assay. In addition, to identify their therapeutic efficacy, we co-cultured HB1.F3.CD or HB1.F3.CD.IFN-b with breast and endometrial cancer cells and cell viability was measured by MTT assay. The engineered stem cells expressed CD and IFN-b genes and several chemoattractant molecules, SCF, CXCR4, VEGF/VEGFR2 and c-kit, were strongly expressed in breast and endometrial cancer cells. These stem cells were effectively migrated to breast and endometrial cancer cells due to chemoattractant molecules secreted by breast and endometrial cancer cells. In therapeutic efficacy, the viability of breast and endometrial cancer cells treated with 5-FC was reduced in the presence of the HB1.F3.CD and HB1.F3.CD.IFN-b cells. Cell viability was more reduced when co-cultured with HB1.F3.CD.IFN-b compared with HB1.F3.CD cells. In conclusion, the results from the present study suggest that genetically modified stem cells expressing CD and IFN-b can be used as a gene-based therapy for treating breast and endometrial cancer via their tumour tropism. This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (No. 2011-0005723).

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Skog, Johan, Ya-Fang Mei et Göran Wadell. « Human adenovirus serotypes 4p and 11p are efficiently expressed in cell lines of neural tumour origin ». Journal of General Virology 83, n^o 6 (1 juin 2002) : 1299–309. http://dx.doi.org/10.1099/0022-1317-83-6-1299.

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Most currently used adenovirus vectors are based upon adenovirus serotypes 2 and 5 (Ad2 and Ad5), which have limited efficiencies for gene transfer to human neural cells. Both serotypes bind to the known adenovirus receptor, CAR (coxsackievirus and adenovirus receptor), and have restricted cell tropism. The purpose of this study was to find vector candidates that are superior to Ad5 in infecting human neural tumours. Using flow cytometry, the vector candidates Ad4p, Ad11p and Ad17p were compared to the commonly used adenovirus vector Ad5v for their binding capacity to neural cell lines derived from glioblastoma, medulloblastoma and neuroblastoma cell lines. The production of viral structural proteins and the CAR-binding properties of the different serotypes were also assessed in these cells. Computer-based models of the fibre knobs of Ad4p and Ad17 were created based upon the crystallized fibre knob structure of adenoviruses and analysed for putative receptor-interacting regions that differed from the fibre knob of Ad5. The non CAR-binding vector candidate Ad11p showed clearly the best binding capacity to all of the neural cell lines, binding more than 90% of cells of all of the neural cell lines tested, in contrast to 20% or less for the commonly used vector Ad5v. Ad4p and Ad11p were also internalized and produced viral proteins more successfully than Ad5. Ad4p showed a low binding ability but a very efficient capacity for infection in cell culture. Ad17p virions neither bound or efficiently infected any of the neural cell lines studied.

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Zhao, T., J. Metcalf et G. Zadeh. « PS2 - 203 Bone Marrow-Derived Mesenchymal Stem Cells Reverse Ionizing Radiation-Induced Active State of Endothelial Cells in Glioblastoma ». Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 43, S4 (octobre 2016) : S15. http://dx.doi.org/10.1017/cjn.2016.373.

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As the central component of heightened vascularization in glioblastoma (GBM), endothelial cells (EC) are arguably the most responsive stromal cells in the tumour microenvironment during conventional treatment using ionizing radiation (IR). Although the inherent tumor tropism and angiogenic property of mesenchymal stem cells (MSC) has been documented in many cancer types including GBM, little is known about the function of MSC that are recruited to the GBM tumor microenvironment. The purpose of this study was to elucidate the effect of MSC on irradiated EC. Here we studied the influence of IR, MSC or MSC condition media (CM) on human umbilical vein endothelial cells (HUVECs). IR was found to up-regulate mRNA levels of CXCL5, CXCL10, ICAM1, VCAM1, VEGF-c and tissue factor (TF) in a dose-dependent manner whereas MSC co-culture boosted the expression of ICAM1, VCAM1, VEGF-c, TF, and MCP3. An additive effect of IR and MSC-culture was most detected with respect to ICAM1, TF and CXCL5 under 2Gy. MSC co-culture decreased IR-induced phospho-p53 in HUVECs at 15Gy. In addition, IR decreased the level of phospho-Akt in HUVECs as well as cell proliferation. Notably, both effects were countered by MSC CM. Interestingly, up-regulation of the same set of IR-driven genes in GBM was positively correlated with poor survival in the TCGA GBM database, a correlation that was lost if using gene list that was obtained from IR and MSC combine. These findings suggest that MSC promotes angiogenesis in GBM by overturning the IR-induced active state of endothelial cells and rendering them radio-resistant.

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Díaz, Mario, Fernando Lobo, Dácil Hernández, Ángel Amesty, Catalina Valdés-Baizabal, Ana Canerina-Amaro, Fátima Mesa-Herrera et al. « FLTX2 : A Novel Tamoxifen Derivative Endowed with Antiestrogenic, Fluorescent, and Photosensitizer Properties ». International Journal of Molecular Sciences 22, n^o 10 (19 mai 2021) : 5339. http://dx.doi.org/10.3390/ijms22105339.

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Tamoxifen is the most widely used selective modulator of estrogen receptors (SERM) and the first strategy as coadjuvant therapy for the treatment of estrogen-receptor (ER) positive breast cancer worldwide. In spite of such success, tamoxifen is not devoid of undesirable effects, the most life-threatening reported so far affecting uterine tissues. Indeed, tamoxifen treatment is discouraged in women under risk of uterine cancers. Recent molecular design efforts have endeavoured the development of tamoxifen derivatives with antiestrogen properties but lacking agonistic uterine tropism. One of this is FLTX2, formed by the covalent binding of tamoxifen as ER binding core, 7-nitrobenzofurazan (NBD) as the florescent dye, and Rose Bengal (RB) as source for reactive oxygen species. Our analyses demonstrate (1) FLTX2 is endowed with similar antiestrogen potency as tamoxifen and its predecessor FLTX1, (2) shows a strong absorption in the blue spectral range, associated to the NBD moiety, which efficiently transfers the excitation energy to RB through intramolecular FRET mechanism, (3) generates superoxide anions in a concentration- and irradiation time-dependent process, and (4) Induces concentration- and time-dependent MCF7 apoptotic cell death. These properties make FLTX2 a very promising candidate to lead a novel generation of SERMs with the endogenous capacity to promote breast tumour cell death in situ by photosensitization.

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Zhang, Lei-Qing, Ya-Fang Mei et Göran Wadell. « Human adenovirus serotypes 4 and 11 show higher binding affinity and infectivity for endothelial and carcinoma cell lines than serotype 5 ». Journal of General Virology 84, n^o 3 (1 mars 2003) : 687–95. http://dx.doi.org/10.1099/vir.0.18666-0.

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Adenoviruses are promising vectors for human cancer gene therapy. However, the extensively used adenoviruses serotypes 2 and 5 (Ad2 and Ad5) from species C have a major disadvantage in being highly prevalent; thus, most adults have an immunity against the two viruses. Furthermore, the expression of coxsackievirus and adenovirus receptors for Ad2 and Ad5 varies in different cells. This study aims to identify adenovirus serotypes with specific tropism for endothelial cells and epithelial tumour cells. Comparison of the binding affinities of Ad31, Ad11, Ad5, Ad37, Ad4 and Ad41, belonging to species A–F, respectively, to established cell lines of hepatoma (HepG2), breast cancer (CAMA and MG7), prostatic cancer (DU145 and LNCaP) and laryngeal cancer (Hep2), as well as to endothelial cells (HMEC), was carried out by flow cytometric analysis. Ad11 from species B showed markedly higher binding affinity than Ad5 for the endothelial cell line and all carcinoma cell lines studied. Ad4 showed a specific binding affinity for hepatoma cells and laryneal carcinoma cells. The ability of Ad11, Ad4 and Ad5 to be expressed in hepatoma, breast cancer and endothelial cell lines was studied by immunostaining and 35S-labelling of viral proteins in infected cells. Ad11 and Ad4 manifested a higher proportion of infected cells and a higher degree of hexon expression than Ad5.

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Naumer, Matthias, Ruth Popa-Wagner et Jürgen A. Kleinschmidt. « Impact of capsid modifications by selected peptide ligands on recombinant adeno-associated virus serotype 2-mediated gene transduction ». Journal of General Virology 93, n^o 10 (1 octobre 2012) : 2131–41. http://dx.doi.org/10.1099/vir.0.044735-0.

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Vectors based on adeno-associated virus serotype 2 (AAV2) belong to today’s most promising and most frequently used viral vectors in human gene therapy. Like in many other vector systems, the broad but non-specific tropism limits their use for certain cell types or tissues. One approach to screen for transduction-improved vectors is the selection of random peptide libraries displayed directly on the AAV2 capsid. Although the AAV2 library system has been widely applied for the successful selection of improved gene therapy vectors, it remains unknown which steps of the transduction process are most affected and therefore critical for the selection of targeting peptides. Attachment to the cell surface is the first essential step of AAV-mediated gene transduction; however, our experiments challenge the conventional belief that enhanced gene transfer is equivalent to more efficient cell binding of recombinant AAV2 vectors. A comparison of the various steps of gene transfer by vectors carrying a wild-type AAV2 capsid or displaying two exemplary peptide ligands selected from AAV2 random libraries on different human tumour cell lines demonstrated strong alterations in cell binding, cellular uptake, as well as intracellular processing of these vectors. Combined, our results suggest that entry and post-entry events are decisive for the selection of the peptides NDVRSAN and GPQGKNS rather than their cell binding efficiency.

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Sethna, Zachary, Marta Luksza, Luis Rojas, Kevin Soares, Joanne Leung, Jayon Lihm, David Hoyos et al. « 824 High quality neoantigens are immunoedited in long-term pancreatic cancer survivors ». Journal for ImmunoTherapy of Cancer 9, Suppl 2 (novembre 2021) : A862. http://dx.doi.org/10.1136/jitc-2021-sitc2021.824.

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BackgroundCancer immunoediting predicts that T cells selectively kill tumor cells expressing immunogenic mutations (neoantigens) resulting in less immunogenic clones to outgrow in tumors.1 Although established through longitudinal studies of how tumors evolve in immune-proficient and -deficient mice,1 2 whether the human immune system naturally targets neoantigens to edit tumors, and the principles that identify the edited neoantigens, remains unclear.MethodsTo investigate if immune selective pressures on neoantigens alter how human tumors evolve, we longitudinally studied how 70 human pancreatic ductal adenocarcinomas (PDACs) - a poorly immunogenic cancer largely presumed to not be subject to immunoediting - evolved over 10 years. We use exome sequencing, neoantigen identification, and clonal reconstruction to compare how primary PDACs evolve to recurrence in rare long-term PDAC survivors previously shown to have more immunogenic tumors3 (n = 9 patients, n = 9 primary, 22 recurrent tumors), to short-term survivors with less immunogenic primary tumors (n = 6 patients, n = 6 primary, 33 recurrent tumors). To identify immunogenic “high quality” neoantigens, we use neopeptide-T cell functional assays and computational modeling to extend and apply a previously developed neoantigen quality model3 4 by predicting high quality neoantigens as arising from amino acid substitutions with sufficient antigenic distance from cognate wild-type peptides to differentially bind the MHC or activate a T cell.ResultsCompared to short-term survivors, we observe that long-term survivors evolve fewer recurrent tumors with longer latency, and distinct tissue tropism. To evaluate if differential immune pressures explained these differences, we discover that despite longer times to evolve, long-term survivors evolve genetically less heterogeneous tumors with fewer clones, fewer nonsynonymous mutations, and fewer neoantigens. To identify if high quality neoantigens are selectively edited in recurrent tumors of long-term survivors, we observe that neoantigens with greater antigenic distance (“less self”) are more depleted in primary and recurrent tumors of long- compared to short-term survivors. Furthermore, we find that long-term survivors evolve markedly fewer new neoantigens of strikingly lower quality, to indicate clones with high quality neoantigens are immunoedited.ConclusionsWe submit longitudinal evidence that the human immune system naturally edits neoantigens in PDAC. Furthermore, we present a model that describes how cancer neoantigens evolve under immune pressure over time, with implications for cancer biology and therapy. More broadly, our results argue that immunoediting is a fundamental cancer suppressive mechanism that can be quantified to predict tumor evolution.AcknowledgementsThis work was supported by NIH U01 CA224175 (V.P.B), a Stand Up to Cancer Convergence Award (B.D.G, V.P.B.), a Damon Runyon Clinical Investigator Award (V.P.B), and the Avner Pancreatic Cancer Foundation (A.J, A.G). Services by the Integrated Genomics Core were funded by the NCI Cancer Center Support Grant (P30 CA08748), Cycle for Survival, and the Marie-Josée and Henry R. Kravis Center for Molecular Oncology.ReferencesShankaran V, et al. IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 2001;410:1107–1111.Matsushita H, et al. Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting. Nature 2012;482:400–404.Balachandran VP, et al. Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. Nature 2017;551:512–516.Łuksza M, et al. A neoantigen fitness model predicts tumour response to checkpoint blockade immunotherapy. Nature 2017;551:517–520.Ethics ApprovalThis study was performed in strict compliance with all institutional ethical regulations and approved by the institutional review boards of Memorial Sloan Kettering Cancer Center (MSK), the Garvan Institute of Medical Research, and the The Johns Hopkins Hospital (JHH). We obtained informed consent from all patients.

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Nor Rashid, Nurshamimi, Rohana Yusof et Roger J. Watson. « Disruption of repressive p130–DREAM complexes by human papillomavirus 16 E6/E7 oncoproteins is required for cell-cycle progression in cervical cancer cells ». Journal of General Virology 92, n^o 11 (1 novembre 2011) : 2620–27. http://dx.doi.org/10.1099/vir.0.035352-0.

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Human papillomaviruses (HPVs) with tropism for mucosal epithelia are the major aetiological factors in cervical cancer. Most cancers are associated with so-called high-risk HPV types, in particular HPV16, and constitutive expression of the HPV16 E6 and E7 oncoproteins is critical for malignant transformation in infected keratinocytes. E6 and E7 bind to and inactivate the cellular tumour suppressors p53 and Rb, respectively, thus delaying differentiation and inducing proliferation in suprabasal keratinocytes to enable HPV replication. One member of the Rb family, p130, appears to be a particularly important target for E7 in promoting S-phase entry. Recent evidence indicates that p130 regulates cell-cycle progression as part of a large protein complex termed DREAM. The composition of DREAM is cell cycle-regulated, associating with E2F4 and p130 in G0/G1 and with the B-myb transcription factor in S/G2. In this study, we addressed whether p130–DREAM is disrupted in HPV16-transformed cervical cancer cells and whether this is a critical function for E6/E7. We found that p130–DREAM was greatly diminished in HPV16-transformed cervical carcinoma cells (CaSki and SiHa) compared with control cell lines; however, when E6/E7 expression was targeted by specific small hairpin RNAs, p130–DREAM was reformed and the cell cycle was arrested. We further demonstrated that the profound G1 arrest in E7-depleted CaSki cells was dependent on p130–DREAM reformation by also targeting the expression of the DREAM component Lin-54 and p130. The results show that continued HPV16 E6/E7 expression is necessary in cervical cancer cells to prevent cell-cycle arrest by a repressive p130–DREAM complex.

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Yi, B. R., S. U. Kim et K. C. Choi. « 126 POTENTIAL EFFECTS OF ENGINEERED STEM CELLS TRANSDUCED WITH THERAPEUTIC GENES AGAINST HeLa HUMAN CERVICAL CANCER CELLS VIA A SELECTIVE TUMOR TROPISM CAUSED BY VASCULAR ENDOTHELIAL GROWTH FACTOR ». Reproduction, Fertility and Development 26, n^o 1 (2014) : 177. http://dx.doi.org/10.1071/rdv26n1ab126.

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According to the World Health Organization, cancer of cervix uteri is the second most common cancer among women worldwide. Recently, cervical cancer still remains a significant public health problem for women despite the development of the human papilloma virus vaccine. The aim of the present study was to investigate the therapeutic efficacy of genetically engineered stem cells (GESTEC) expressing bacterial cytosine deaminase (CD), human interferon-β (IFN-b) gene, or both against HeLa human cervical cancer and the migration factors of the GESTEC toward the cancer cells. A continuously dividing immortalized cell line of neural stem cells (NSC) from a single clone of human fetal brain, HB1.F3, was developed by introducing v-myc. The further introduction of these NSC with bacterial CD and human IFN-b resulted in the generation of HB1.F3.CD and HB1.F3.CD.IFN-b cells. The anticancer effect of these GESTEC was examined in a co-culture with HeLa cells using MTT assay to measure cell viability. A transwell migration assay was performed to assess the migration capability of the stem cells to cervical cancer cells. Next, several chemoattractant ligands and their receptors related to a selective migration of the stem cells towards HeLa cells were determined by real-time PCR. The cell viability of HeLa cells was decreased in response to 5-fluorocytosine (5-FC), a prodrug, indicating that 5-fluorouracil (5-FU), a toxic metabolite, was converted from 5-FC by the CD gene and it caused the cell death in a co-culture system. When IFN-b was additionally expressed with the CD gene by these GESTEC, the anticancer activity was significantly increased. In the migration assay, the GESTEC selectively migrated to HeLa cells. As results of real-time PCR, chemoattractant ligands such as MCP-1, SCF, and VEGF were expressed in HeLa cells, and several receptors such as uPAR, VEGFR2, and c-kit were produced by the GESTEC. These GESTEC transduced with the CD gene and IFN-b may provide the potential of a novel gene therapy for anti-cervical cancer treatments via their selective tumour tropism derived from VEGF and VEGFR2 expressions between HeLa cells and the GESTEC. This work was supported by a grant from the Next-Generation BioGreen 21 Program (No. PJ009599), Rural Development Administration, Republic of Korea.

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Patel, Bella, Ehsan Ghorani, Y. Zhang, R. Gitendra-Wickremasinghe, Andrew Steele et Adele K. Fielding. « Attenuated Measles Virus : A Promising Therapeutic Modality for B Cell Malignancy. » Blood 114, n^o 22 (20 novembre 2009) : 2460. http://dx.doi.org/10.1182/blood.v114.22.2460.2460.

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Abstract Abstract 2460 Poster Board II-437 Replicating viruses that selectively lyse transformed cells are promising agents for cancer therapy. Attenuated measles virus (MV) has particular tropism for B cells and is oncolytic in murine models of myeloma and lymphoma. These results have led to phase 1 studies in myeloma. Here we investigated the anti-tumour potential of MV in adult B lineage acute lymphoblastic leukaemia (ALL) and Chronic lymphocytic leukaemia (CLL). GFP expressing attenuated MV derived from the Edmonston vaccine lineage (MV-Edm) was used to infect ALL (n = 6) or chronic lymphocytic leukaemia (CLL, n = 7) primary specimens. All CLL and ALL cells expressed the MV receptor CD46. The second MV receptor SLAM was consistently expressed in all the CLL cells but only in 5/6 of the ALL cells. Both ALL and CLL cells were efficiently infected by MV-Edm as indicated by quantitation of viral nucleocapsid mRNA by RQ-PCR and immunoblotting of viral proteins N,H and F. Large multinucleated syncytia, characteristic of MV- induced cytopathology, were found in all infected ALL cultures (Figure 1), by contrast syncitium formation was less prominent in the infected CLL specimens. Despite this, both CLL and ALL cells were efficiently killed by MV-Edm, as characterised by FACS and trypan blue based assays as well as immunoblotting for PARP cleavage. Specificity of lysis for tumor cells was confrmed by infection of normal mononuclear cell controls, which showed minimal syncitium formation and death even after prolonged infection. To investigate the contribution of cell-to-cell fusion in the pathogenesis of MV-induced oncolysis we investigated a relatively non-fusogenic MV:MV-Moraten in our models. Surprisingly, both CLL and ALL cultures infected with MV-Moraten demonstrated a reduction in cell viability compared to uninfected controls despite the absence of typical features of MV cytopathology. Our data suggest that both ALL and CLL are targets for MV-mediated lysis and that cell-cell- fusion might not be an important determinant of this effect in-vitro. Ongoing in vivo studies of MV oncolysis in B-cell malignancy should further inform the therapeutic potential of vaccine MV for these neoplasms. Figure 1 MV-Edm infection results in prominent syncytia formation in primary ALL cells (A and B). Figure 1. MV-Edm infection results in prominent syncytia formation in primary ALL cells (A and B). Disclosures: No relevant conflicts of interest to declare.

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M. Gordon, Erlinda, Seiya Liu, Sant P. Chawla et Frederick L. Hall. « Polypeptidic Taxol-Tropins : Targeting paclitaxel to the tumor microenvironment ». Cancer Research and Cellular Therapeutics 5, n^o 3 (26 juillet 2021) : 01–11. http://dx.doi.org/10.31579/2640-1053/089.

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Background and Rationale: Although PTX is widely used as a single chemotherapeutic agent and in various combination regimens, its clinical utility is hindered by acquired drug resistance and serious dose-limiting side effects that result from the ungoverned biodistribution of the taxane. Hypothesis: Conceptually, the precision, validity, and efficiency of paclitaxel delivery to tumor compartments might be substantially improved by “actively targeting” the exposed collagenous (XC-) proteins presented within the tumor microenvironment (TME)—XC-proteins physically exposed by the pathologic biochemical processes of tumor invasion, reactive stroma formation, and neo-angiogenesis. Objective: An adaptive bioengineering approach aims to apply pathotropic tumor-targeting functionality to paclitaxel (PTX), a powerful cytotoxic taxane which exhibits anti-tubulin / anti-mitotic / anti-cancer activities against a broad range of solid tumors. Materials and Methods: Synthetic peptide XC-targeting probes (< 40 aa) and polypeptide aptamers (40 to 53 aa), 85 - 99% purity, were prepared by 9-fluorenylmethyloxycarbonyl (Fmoc) solid phase peptide synthesis, purified by high performance liquid chromatography (HPLC), and verified by mass spectrometry and amino acid analysis, and the XC-targeting probes were FITC-labeled. Analysis of fluorescence in XC-binding assays was visualized with an Ultra Bright Blue Light trans-illuminator equipped with an amber filter; photo-documentation was provided by a Leica V-Lux 1 digital camera; and comparative fluorescence was quantified using a Quantus benchtop fluorimeter (Promega). The tumor-targeting properties of Taxol-Tropins were tested in vitro by Taxol-aptamer binding assays and collagen-agarose binding assays and the bioactivities of PTX bound non-covalently toTaxol-Tropin aptamers were tested on XC-agarose beads. Further, the tumor targeting property of the Taxol-Tropin aptamers was tested in vivo in a murine model of metastatic cancer. Results: Here we report on the first actively targeted delivery of paclitaxel utilizing bifunctional polypeptide targeting onco-aptamers, called Taxol-Tropins, which: (i) bind PTX upon simple mixing with suitably high affinities and; (ii) bind exposed XC-proteins, thereby promoting enhanced partitioning and drug delivery into the TME. The bifunctional peptide sequence-optimized Taxol-Tropins bound tightly non-covalently to PTX and also exhibited high affinity and selectivity for XC-agarose beads in vitro. Importantly, the cytotoxic bioactivity of the Taxol-Tropin-bound-PTX molecule was well preserved in cellulo, as was demonstrated by cytocidal activity observed in MDA-MB-231 breast cancer cell cultures. Tumor-targeted PTX delivery by Taxol-Tropin onco-aptamers in vivo was modeled by subcutaneous xenografts of human pancreatic cancer in nude mice: where intense fluorescence of the PTX probe was observed in tumors of mice injected with the Taxol-Tropin-bound-PTX within minutes after intravenous injection, but not in untreated mice or mice treated with non-targeted PTX probe. Conclusions: These results demonstrate the feasibility of pro-actively targeting PTX, a clinically important small molecule, using Taxol-Tropins: synthetic polypeptide onco-aptamers, revealing optimized drug binding sequences and structural modifications pertinent to further clinical development of the tumor-targeting platform which may indeed shift the Therapeutic Index of PTX to one of greater clinical efficacy at lower drug doses.

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Malaguarnera, Roberta, Alaide Morcavallo et Antonino Belfiore. « The Insulin and IGF-I Pathway in Endocrine Glands Carcinogenesis ». Journal of Oncology 2012 (2012) : 1–19. http://dx.doi.org/10.1155/2012/635614.

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Endocrine cancers are a heterogeneous group of diseases that may arise from endocrine cells in any gland of the endocrine system. These malignancies may show an aggressive behavior and resistance to the common anticancer therapies. The etiopathogenesis of these tumors remains mostly unknown. The normal embryological development and differentiation of several endocrine glands are regulated by specific pituitary tropins, which, in adult life, control the function and trophism of the endocrine gland. Pituitary tropins act in concert with peptide growth factors, including the insulin-like growth factors (IGFs), which are considered key regulators of cell growth, proliferation, and apoptosis. While pituitary TSH is regarded as tumor-promoting factor for metastatic thyroid cancer, the role of other pituitary hormones in endocrine cancers is uncertain. However, multiple molecular abnormalities of the IGF system frequently occur in endocrine cancers and may have a role in tumorigenesis as well as in tumor progression and resistance to therapies. Herein, we will review studies indicating a role of IGF system dysregulation in endocrine cancers and will discuss the possible implications of these findings for tumor prevention and treatment, with a major focus on cancers from the thyroid, adrenal, and ovary, which are the most extensively studied.

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Yudintceva, Natalia, Ekaterina Lomert, Natalia Mikhailova, Elena Tolkunova, Nikol Agadzhanian, Konstantin Samochernych, Gabriele Multhoff et al. « Targeting Brain Tumors with Mesenchymal Stem Cells in the Experimental Model of the Orthotopic Glioblastoma in Rats ». Biomedicines 9, n^o 11 (1 novembre 2021) : 1592. http://dx.doi.org/10.3390/biomedicines9111592.

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Despite multimodal approaches for the treatment of multiforme glioblastoma (GBM) advances in outcome have been very modest indicating the necessity of novel diagnostic and therapeutic strategies. Currently, mesenchymal stem cells (MSCs) represent a promising platform for cell-based cancer therapies because of their tumor-tropism, low immunogenicity, easy accessibility, isolation procedure, and culturing. In the present study, we assessed the tumor-tropism and biodistribution of the superparamagnetic iron oxide nanoparticle (SPION)-labeled MSCs in the orthotopic model of C6 glioblastoma in Wistar rats. As shown in in vitro studies employing confocal microscopy, high-content quantitative image cytometer, and xCelligence system MSCs exhibit a high migratory capacity towards C6 glioblastoma cells. Intravenous administration of SPION-labeled MSCs in vivo resulted in intratumoral accumulation of the tagged cells in the tumor tissues that in turn significantly enhanced the contrast of the tumor when high-field magnetic resonance imaging was performed. Subsequent biodistribution studies employing highly sensitive nonlinear magnetic response measurements (NLR-M2) supported by histological analysis confirm the retention of MSCs in the glioblastoma. In conclusion, MSCs due to their tumor-tropism could be employed as a drug-delivery platform for future theranostic approaches.

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Kenmochi, Hiroaki, Tomohiro Yamasaki, Tomoya Oishi, Makoto Horikawa, Taisuke Yamamoto, Shinichiro Koizumi, Tetsuro Sameshima et Hiroki Namba. « CBMS-08 INVESTIGATION FOR NICOTINIC EFFECTS ON STEM CELL’S PROPERTY IN HSV-TK/GCV GENE THERAPY ». Neuro-Oncology Advances 1, Supplement_2 (décembre 2019) : ii6. http://dx.doi.org/10.1093/noajnl/vdz039.027.

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Abstract BACKGROUND Herpes simplex virus-thymidine kinase/ganciclovir (HSV-tk/GCV) system is one of feasible therapeutic strategies for defeating malignant gliomas. Stem cells with intrinsic tumor tropism are used for suicide gene vehicles, which make this therapy further realistic. Nicotine is known to affect cellular migration capacity in variety types of cells but whether nicotine impacts on stem cells’ migration capacity to gliomas is not scrutinized. In this research, we investigated nicotinic impact on stem cells’ properties including tumor tropism and gap junctional intercellular communication (GJIC), which is crucial to this therapeutic strategy. METHODS Mouse induced pluripotent stem cell (iPSC)-derived neural stem cells (miPS-NSCs) and human dental pulp mesenchymal stem cells (hDPSCs) were used. Nicotine cytotoxicity for 24 hours was evaluated by MTT assay for stem cells and glioma cells; GS-9L and C6 (rat), GL261 (mouse), U251 and U87 (human). Tumor tropism to glioma-conditioned medium (CM) with or without non-toxic nicotine concentrations was assessed using Matrigel Invasion Chamber. Nicotine effect on GJIC was assessed with scrape loading/dye transfer assay (SL/DT assay) for co-culture of stem cells and glioma cells (stem cell/glioma cell) or parachute assay for glioma cells alone using high-content analysis. RESULTS MTT assay revealed 1 μM of nicotine, equivalent to serum nicotine concentration in habitual smoking, is the maximum safe concentration for stem cells and glioma cells. Tumor tropism (miPS-NSCs to GL261-CM, hDPSCs to U251- or U87-CM) and GJIC of co-culture of stem cells and glioma cells (miPS-NSC/GL261, hDPSC/U251) or glioma cells alone (GS-9L, C6, GL261 and U251) were not affected by 1 μM of nicotine. CONCLUSIONS Physiological nicotine presence did not affect (1) stem cell’s tumor tropism to gliomas and (2) GJIC between stem cells and glioma cells or within glioma cells. HSV-tk/GCV therapy may retain its therapeutic efficacy against gliomas even under physiological nicotine concentrations.

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Mortezaee, Keywan. « Organ tropism in solid tumor metastasis : an updated review ». Future Oncology 17, n^o 15 (mai 2021) : 1943–61. http://dx.doi.org/10.2217/fon-2020-1103.

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Tumors are equipped with a highly complex machinery of interrelated events so as to adapt to hazardous conditions, preserve a growing cell mass and thrive at the site of metastasis. Tumor cells display metastatic propensity toward specific organs where the stromal milieu is appropriate for their further colonization. Effective colonization relies on the plasticity of tumor cells in adapting to the conditions of the new area by reshaping their epigenetic landscape. Breast cancer cells, for instance, are able to adopt brain-like or epithelial/osteoid features in order to pursue effective metastasis into brain and bone, respectively. The aim of this review is to discuss recent insights into organ tropism in tumor metastasis, outlining potential strategies to address this driver of tumor aggressiveness.

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Gao, Yu, Yaqi Wang, Afu Fu, Wei Shi, David Yeo, Kathy Qian Luo, Hooisweng Ow et Chenjie Xu. « Tracking mesenchymal stem cell tumor-homing using fluorescent silica nanoparticles ». Journal of Materials Chemistry B 3, n^o 7 (2015) : 1245–53. http://dx.doi.org/10.1039/c4tb01452a.

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Stanford, Marianne M., John W. Barrett, Steven H. Nazarian, Steven Werden et Grant McFadden. « Oncolytic Virotherapy Synergism with Signaling Inhibitors : Rapamycin Increases Myxoma Virus Tropism for Human Tumor Cells ». Journal of Virology 81, n^o 3 (15 novembre 2006) : 1251–60. http://dx.doi.org/10.1128/jvi.01408-06.

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ABSTRACT Myxoma virus is a rabbit-specific poxvirus pathogen that also exhibits a unique tropism for human tumor cells and is dramatically oncolytic for human cancer xenografts. Most tumor cell lines tested are permissive for myxoma infection in a fashion intimately tied to the activation state of Akt kinase. A host range factor of myxoma virus, M-T5, directly interacts with Akt and mediates myxoma virus tumor cell tropism. mTOR is a regulator of cell growth and metabolism downstream of Akt and is specifically inhibited by rapamycin. We report that treatment of nonpermissive human tumor cell lines, which normally restrict myxoma virus replication, with rapamycin dramatically increased virus tropism and spread in vitro. This increased myxoma replication is concomitant with global effects on mTOR signaling, specifically, an increase in Akt kinase. In contrast to the effects on human cancer cells, rapamycin does not increase myxoma virus replication in rabbit cell lines or permissive human tumor cell lines with constitutively active Akt. This indicates that rapamycin increases the oncolytic capacity of myxoma virus for human cancer cells by reconfiguring the internal cell signaling environment to one that is optimal for productive virus replication and suggests the possibility of a potentially therapeutic synergism between kinase signaling inhibitors and oncolytic poxviruses for cancer treatment.

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Kines, Rhonda C., et John T. Schiller. « Harnessing Human Papillomavirus’ Natural Tropism to Target Tumors ». Viruses 14, n^o 8 (28 juillet 2022) : 1656. http://dx.doi.org/10.3390/v14081656.

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Human papillomaviruses (HPV) are small non-enveloped DNA tumor viruses established as the primary etiological agent for the development of cervical cancer. Decades of research have elucidated HPV’s primary attachment factor to be heparan sulfate proteoglycans (HSPG). Importantly, wounding and exposure of the epithelial basement membrane was found to be pivotal for efficient attachment and infection of HPV in vivo. Sulfation patterns on HSPG’s become modified at the site of wounds as they serve an important role promoting tissue healing, cell proliferation and neovascularization and it is these modifications recognized by HPV. Analogous HSPG modification patterns can be found on tumor cells as they too require the aforementioned processes to grow and metastasize. Although targeting tumor associated HSPG is not a novel concept, the use of HPV to target and treat tumors has only been realized in recent years. The work herein describes how decades of basic HPV research has culminated in the rational design of an HPV-based virus-like infrared light activated dye conjugate for the treatment of choroidal melanoma.

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Tang, Kai, Ying Xin, Keming Li, Xi Chen et Youhua Tan. « Cell Cytoskeleton and Stiffness Are Mechanical Indicators of Organotropism in Breast Cancer ». Biology 10, n^o 4 (25 mars 2021) : 259. http://dx.doi.org/10.3390/biology10040259.

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Tumor metastasis involves the dissemination of tumor cells from the primary lesion to other organs and the subsequent formation of secondary tumors, which leads to the majority of cancer-related deaths. Clinical findings show that cancer cell dissemination is not random but exhibits organ preference or organotropism. While intrinsic biochemical factors of cancer cells have been extensively studied in organotropism, much less is known about the role of cell cytoskeleton and mechanics. Herein, we demonstrate that cell cytoskeleton and mechanics are correlated with organotropism. The result of cell stiffness measurements shows that breast cancer cells with bone tropism are much stiffer with enhanced F-actin, while tumor cells with brain tropism are softer with lower F-actin than their parental cells. The difference in cellular stiffness matches the difference in the rigidity of their metastasized organs. Further, disrupting the cytoskeleton of breast cancer cells with bone tropism not only elevates the expressions of brain metastasis-related genes but also increases cell spreading and proliferation on soft substrates mimicking the stiffness of brain tissue. Stabilizing the cytoskeleton of cancer cells with brain tropism upregulates bone metastasis-related genes while reduces the mechanoadaptation ability on soft substrates. Taken together, these findings demonstrate that cell cytoskeleton and biophysical properties of breast cancer subpopulations correlate with their metastatic preference in terms of gene expression pattern and mechanoadaptation ability, implying the potential role of cell cytoskeleton in organotropism.

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Chung, Tsai-Hua, Chia-Chu Hsieh, Jong-Kai Hsiao, Szu-Chun Hsu, Ming Yao et Dong-Ming Huang. « Dextran-coated iron oxide nanoparticles turn protumor mesenchymal stem cells (MSCs) into antitumor MSCs ». RSC Advances 6, n^o 51 (2016) : 45553–61. http://dx.doi.org/10.1039/c6ra03453e.

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Bupp, Keith, Anindita Sarangi et Monica J. Roth. « Probing Sequence Variation in the Receptor-Targeting Domain of Feline Leukemia Virus Envelope Proteins with Peptide Display Libraries ». Journal of Virology 79, n^o 3 (1 février 2005) : 1463–69. http://dx.doi.org/10.1128/jvi.79.3.1463-1469.2005.

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ABSTRACT Determinants of cellular tropism and receptor targeting lie within a short peptide in the Vr1 region of the envelope (Env) proteins of feline leukemia virus (FeLV) subgroups A and C. Libraries of FeLV Env proteins with random amino acid substitutions in the peptide were screened for their ability to deliver a marker gene to D17 and AH927 cells. Screening on D17 canine cells yielded D17-specific Env proteins that used the FeLV-C receptor. Screening on AH927 cells yielded Env proteins with a broader host range, with maximal titers on AH927 cells and similar or lower titers on other cells. These Env proteins used an unidentified non-FeLV receptor for entry. The A5 isolate obtained from the AH927 screen was readily concentrated to yield titers of 105 on human PC-3 prostate tumor cells. The sequence divergence observed among targeting peptides of library-selected Env proteins was greater than that found in parental FeLV isolates. Substitution analyses of a conserved R in the middle of the targeting peptide held constant during screening indicated that maximal titers were obtained only when R was present in both a D17 selected isolate and an AH927 selected isolate. The ability to isolate Env proteins with unique tropisms dependent on the cells on which the library is screened has direct implications for targeting gene delivery vectors.

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Gordon, Benjamin, Bhairavi Swaminathan, LA Naiche et Jan Kitajewski. « Abstract P6-14-10 : Jagged-1 promotes breast cancer metastasis through the lymphatic system ». Cancer Research 83, n^o 5_Supplement (1 mars 2023) : P6–14–10—P6–14–10. http://dx.doi.org/10.1158/1538-7445.sabcs22-p6-14-10.

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Abstract While early detection of breast cancer (BC) has improved prognoses, there is an urgent need to improve outcomes for patients with distant metastatic disease. Higher expression of the Notch ligand JAG1 in primary BC tumors is strongly associated with lymph node metastasis and patient mortality, but causality is unclear. We show that JAG1 expression is higher in patients’ metastatic BC cells colonizing lymph nodes than in primary tumors, suggesting that tumor cells with high JAG1 are preferentially able to metastasize to lymph nodes. JAG1 expression is higher in a derivative of BC line MDA-MB-231 selected for tropism to lymph nodes (MDA231-LN) than in the parental line or derivatives with other tropisms. To determine the mechanism(s) of JAG1-mediated metastasis, we generated clonal JAG1 knockout cell lines from MDA231-LN cells with corresponding JAG1 rescue lines. We investigated the role of JAG1 in spontaneous metastasis under clinically relevant conditions by orthotopically implanting JAG1 knockout and expressing cells, resecting the primary tumor, and following long-term metastatic spread in a mouse model. Quantification of tumor cells in blood showed that survival, metastatic burden, and JAG1 expression did not correlate with the number of circulating tumor cells. Conversely, JAG1 expression drove an increase in lymph node and body-wide metastatic burden and a trend toward decreased survival. In this model metastatic cells were abundant throughout lymph vessels, suggesting lymphatics are the primarily route of dissemination. Preliminary transcriptional analysis suggests that JAG1 alters interactions with lymphatic endothelial cells (LEC), potentially via VEGF signaling, leading us to examine downstream events in co-cultures of LEC with lymphatically invasive BC lines. Deciphering tumor-lymphatic endothelial signaling events may open new avenues to target BC metastasis. Citation Format: Benjamin Gordon, Bhairavi Swaminathan, LA Naiche, Jan Kitajewski. Jagged-1 promotes breast cancer metastasis through the lymphatic system [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-14-10.

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Mishra, Ameet K., Iris Kemler et David Dingli. « Development of CAR-T Cell Constructs with Broad Anti-Tumor Tropism ». Blood 136, Supplement 1 (5 novembre 2020) : 24. http://dx.doi.org/10.1182/blood-2020-136704.

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Chimeric antigen receptor T (CAR-T) cell therapy is a transformative approach to cancer eradication. CAR-T is expensive in part due to the restricted use of each CAR construct for a specific set of tumors such as B cell lymphoma targeted with CD19 and multiple myeloma targeted with BCMA. A CAR construct with broad anti-tumor activity can be advantageous due to wide applicability and scalability of production. We show that CD126, the IL-6 receptor alpha, is an antigen that is expressed by many hematologic and solid malignancies including multiple myeloma, non-Hodgkin lymphoma, acute myeloid leukemia, pancreatic and prostate adenocarcinoma, non-small cell lung cancer and malignant melanoma amongst others. High CD126 expression is a negative prognostic marker in many malignancies. The two CD126 targeting CAR-T cell constructs contain the CD28 anchoring domain followed by 4-1BB and CD3 zeta signaling domain. Lentiviral vectors were generated with triple plasmid (CAR, psPAX2 and pMD2.G) transfection of 293T cells and the vector concentrated by ultracentrifugation and used to transduce human T cells. T cells were isolated from leuko-reduction cones using negative selection with magnetic beads. The transduction efficiency was around 60%. The T cells were activated with anti-CD3/CD28 beads and expanded for two weeks before using for downstream experiments. CD126 CAR-T cells are able to kill many tumor cells in an antigen specific manner and with an efficiency that is directly proportional to the cell surface expression of CD126 expression (rho = 0.6, p = 0.0019). The presence of soluble CD126 in the culture media did not interfere with CAR-T cell killing. The CAR-T constructs bind murine CD126. However, injection of CD126 targeting CAR-T cells in NSG mice did not lead to any evidence of hepatotoxicity and weight loss despite possible expression of this antigen on hepatocytes. In vivo studies in NSG mice with multiple myeloma (RPMI-8226) and prostate adenocarcinoma (DU-145) xenograft models (n=10 tumors per group) showed that the intravenously injected CD126 targeted CAR-T cells (107) infiltrated the tumors, expanded, produced human interferon gamma and killed the tumor cells (p<0.001). Bioluminescence imaging showed control of tumor growth in the actively treated tumors compared to the controls (p<0.05). At post mortem, mice injected with CD126 targeted CAR-T cells had smaller residual tumors compared to controls injected with non-engineered human T cells from the same donor. Binding of sIL-6R by CAR-T cells could mitigate cytokine release syndrome. In support of this, murine SAA-3 levels (the equivalent of human CRP) were lower in mice injected with CD126 CAR-T compared to controls (p<0.05), suggesting that binding of sIL-6R by CAR-T cells could mitigate cytokine release syndrome. CD126 provides a novel therapeutic for CAR-T cells in a broad variety of tumors with low risk of toxicity. Disclosures Dingli: Apellis: Consultancy; Millenium: Consultancy; Janssen: Consultancy; Bristol Myers Squibb: Research Funding; Sanofi-Genzyme: Consultancy; Alexion: Consultancy; Rigel: Consultancy; Karyopharm Therapeutics: Research Funding.

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Klotz, Remi, Amal Thomas, Teng Teng, Sung Min Han, Oihana Iriondo, Lin Li, Sara Restrepo-Vassalli et al. « Circulating Tumor Cells Exhibit Metastatic Tropism and Reveal Brain Metastasis Drivers ». Cancer Discovery 10, n^o 1 (10 octobre 2019) : 86–103. http://dx.doi.org/10.1158/2159-8290.cd-19-0384.

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Zhao, D., J. Najbauer, E. Garcia, M. Z. Metz, M. Gutova, C. A. Glackin, S. U. Kim et K. S. Aboody. « Neural Stem Cell Tropism to Glioma : Critical Role of Tumor Hypoxia ». Molecular Cancer Research 6, n^o 12 (1 décembre 2008) : 1819–29. http://dx.doi.org/10.1158/1541-7786.mcr-08-0146.

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Ferreira, Raiane Oliveira, Isabela Granha, Rodolfo Sanches Ferreira, Heloisa de Siqueira Bueno, Oswaldo Keith Okamoto, Carolini Kaid et Mayana Zatz. « Effect of Serial Systemic and Intratumoral Injections of Oncolytic ZIKVBR in Mice Bearing Embryonal CNS Tumors ». Viruses 13, n^o 10 (19 octobre 2021) : 2103. http://dx.doi.org/10.3390/v13102103.

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The Zika virus (ZIKV) has shown a promising oncolytic effect against embryonal CNS tumors. However, studies on the effect of different administration routes and the ideal viral load in preclinical models are highly relevant aiming for treatment safety and efficiency. Here, we investigated the effect and effectiveness of different routes of administration, and the number of ZIKVBR injections on tumor tropism, destruction, and side effects. Furthermore, we designed an early-stage human brain organoid co-cultured with embryonal CNS tumors to analyze the ZIKVBR oncolytic effect. We showed that in the mice bearing subcutaneous tumors, the ZIKVBR systemically presented a tropism to the brain. When the tumor was located in the mice’s brain, serial systemic injections presented efficient tumor destruction, with no neurological or other organ injury and increased mice survival. In the human cerebral organoid model co-cultured with embryonal CNS tumor cells, ZIKVBR impaired tumor progression. The gene expression of cytokines and chemokines in both models suggested an enhancement of immune cells recruitment and tumor inflammation after the treatment. These results open new perspectives for virotherapy using the ZIKVBR systemic administration route and multiple doses of low virus load for safe and effective treatment of embryonal CNS tumors, an orphan disease that urges new effective therapies.

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Lee, Hyeji, Kanghye Bae, Ah-Rum Baek, Eun-Bin Kwon, Yeoun-Hee Kim, Sung-Wook Nam, Gang Ho Lee et Yongmin Chang. « Glioblastoma-Derived Exosomes as Nanopharmaceutics for Improved Glioma Treatment ». Pharmaceutics 14, n^o 5 (6 mai 2022) : 1002. http://dx.doi.org/10.3390/pharmaceutics14051002.

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The use of cancer-derived exosomes has been studied in several cancer types, but the cancer-targeting efficacy of glioma-derived exosomes has not been investigated in depth for malignant glioblastoma (GBM) cells. In this study, exosomes were derived from U87MG human glioblastoma cells, and selumetinib, a new anticancer drug, was loaded into the exosomes. We observed the tropism of GBM-derived exosomes in vitro and in vivo. We found that the tropism of GBM-derived exosomes is in contrast to the behavior of non-exosome-enveloped drugs and non-GBM-specific exosomes in vitro and in vivo in an animal GBM model. We found that the tropism exhibited by GBM-derived exosomes can be utilized to shuttle selumetinib, with no specific targeting moiety, to GBM tumor sites. Therefore, our findings indicated that GBM-derived exosomes loaded with selumetinib had a specific antitumor effect on U87MG cells and were non-toxic to normal brain cells. These exosomes offer improved therapeutic prospects for glioblastoma therapy.

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Bu, Guo-Long, Chu Xie, Yin-Feng Kang, Mu-Sheng Zeng et Cong Sun. « How EBV Infects : The Tropism and Underlying Molecular Mechanism for Viral Infection ». Viruses 14, n^o 11 (27 octobre 2022) : 2372. http://dx.doi.org/10.3390/v14112372.

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The Epstein–Barr virus (EBV) is associated with a variety of human malignancies, including Burkitt’s lymphoma, Hodgkin’s disease, nasopharyngeal carcinoma and gastric cancers. EBV infection is crucial for the oncogenesis of its host cells. The prerequisite for the establishment of infection is the virus entry. Interactions of viral membrane glycoproteins and host membrane receptors play important roles in the process of virus entry into host cells. Current studies have shown that the main tropism for EBV are B cells and epithelial cells and that EBV is also found in the tumor cells derived from NK/T cells and leiomyosarcoma. However, the process of EBV infecting B cells and epithelial cells significantly differs, relying on heterogenous glycoprotein–receptor interactions. This review focuses on the tropism and molecular mechanism of EBV infection. We systematically summarize the key molecular events that mediate EBV cell tropism and its entry into target cells and provide a comprehensive overview.

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Zhou, Jun, Tian Liang, Dejun Wang, Liru Li, Yan Cheng, Qiuyan Guo et Guangmei Zhang. « IFNα-Expressing Amniotic Fluid-Derived Mesenchymal Stem Cells Migrate to and Suppress HeLa Cell-Derived Tumors in a Mouse Model ». Stem Cells International 2018 (2018) : 1–14. http://dx.doi.org/10.1155/2018/1241323.

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Background. Immunotherapy for cervical cancer with type I interferon (IFN) is limited because of the cytotoxicity that accompanies the high doses that are administered. In this study, we investigated the utilization of amniotic fluid-derived mesenchymal stem cells (AF-MSCs) as a means for delivering IFNα to local tumor sites for the suppression of cervical cancer in a mouse model using HeLa cell xenografts. Methods. The tumor tropism ability of AF-MSCs and AF-MSCs genetically modified to overexpress IFNα (IFNα-AF-MSCs) was examined through Transwell in vitro and through fluorescent images and immunohistochemistry in a mouse model. Tumor size and tumor apoptosis were observed to evaluate the efficacy of the targeting therapy. Mechanistically, tumor cell apoptosis was detected by cytometry and TUNEL, and oncogenic proteins c-Myc, p53, and Bcl-2 as well as microvessel density were detected by immunohistochemistry. Results. In this model, intravenously injected AF-MSCs selectively migrated to the tumor sites, participated in tumor construction, and promoted tumor growth. After being genetically modified to overexpress IFNα, the IFNα-AF-MSCs maintained their tumor tropism but could significantly suppress tumor growth. The restrictive efficacy of IFNα-AF-MSCs was associated with the suppression of angiogenesis, inhibition of tumor cell proliferation, and induction of apoptosis in tumor cells. Neither AF-MSCs nor IFNα-AF-MSCs trigger tumor formation. Conclusions. IFNα-AF-MSC-based therapy is feasible and shows potential for treating cervical cancer, suggesting that AF-MSCs may be promising vehicles for delivering targeted anticancer therapy.

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Luo, Yumei, Xuehu Xu, Xiuli An, Xiaofang Sun, Shu Wang et Detu Zhu. « Targeted Inhibition of the miR-199a/214 Cluster by CRISPR Interference Augments the Tumor Tropism of Human Induced Pluripotent Stem Cell-Derived Neural Stem Cells under Hypoxic Condition ». Stem Cells International 2016 (2016) : 1–8. http://dx.doi.org/10.1155/2016/3598542.

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The human induced pluripotent stem cell (hiPSC) provides a breakthrough approach that helps overcoming ethical and allergenic challenges posed in application of neural stem cells (NSCs) in targeted cancer gene therapy. However, the tumor-tropic capacity of hiPSC-derived NSCs (hiPS-NSCs) still has much room to improve. Here we attempted to promote the tumor tropism of hiPS-NSCs by manipulating the activity of endogenous miR-199a/214 cluster that is involved in regulation of hypoxia-stimulated cell migration. We first developed a baculovirus-delivered CRISPR interference (CRISPRi) system that sterically blocked the E-box element in the promoter of the miR-199a/214 cluster with an RNA-guided catalytically dead Cas9 (dCas9). We then applied this CRISPRi system to hiPS-NSCs and successfully suppressed the expression of miR-199a-5p, miR-199a-3p, and miR-214 in the microRNA gene cluster. Meanwhile, the expression levels of their targets related to regulation of hypoxia-stimulated cell migration, such as HIF1A, MET, and MAPK1, were upregulated. Further migration assays demonstrated that the targeted inhibition of the miR-199a/214 cluster significantly enhanced the tumor tropism of hiPS-NSCs both in vitro and in vivo. These findings suggest a novel application of CRISPRi in NSC-based tumor-targeted gene therapy.

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Ho, Chun-Te, Mei-Hsuan Wu, Ming-Jen Chen, Shih-Pei Lin, Yu-Ting Yen et Shih-Chieh Hung. « Combination of Mesenchymal Stem Cell-Delivered Oncolytic Virus with Prodrug Activation Increases Efficacy and Safety of Colorectal Cancer Therapy ». Biomedicines 9, n^o 5 (13 mai 2021) : 548. http://dx.doi.org/10.3390/biomedicines9050548.

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Although oncolytic viruses are currently being evaluated for cancer treatment in clinical trials, systemic administration is hindered by many factors that prevent them from reaching the tumor cells. When administered systemically, mesenchymal stem cells (MSCs) target tumors, and therefore constitute good cell carriers for oncolytic viruses. MSCs were primed with trichostatin A under hypoxia, which upregulated the expression of CXCR4, a chemokine receptor involved in tumor tropism, and coxsackievirus and adenovirus receptor that plays an important role in adenoviral infection. After priming, MSCs were loaded with conditionally replicative adenovirus that exhibits limited proliferation in cells with a functional p53 pathway and encodes Escherichia coli nitroreductase (NTR) enzymes (CRAdNTR) for targeting tumor cells. Primed MSCs increased tumor tropism and susceptibility to adenoviral infection, and successfully protected CRAdNTR from neutralization by anti-adenovirus antibodies both in vitro and in vivo, and specifically targeted p53-deficient colorectal tumors when infused intravenously. Analyses of deproteinized tissues by UPLC-MS/QTOF revealed that these MSCs converted the co-administered prodrug CB1954 into cytotoxic metabolites, such as 4-hydroxylamine and 2-amine, inducing oncolysis and tumor growth inhibition without being toxic for the host vital organs. This study shows that the combination of oncolytic viruses delivered by MSCs with the activation of prodrugs is a new cancer treatment strategy that provides a new approach for the development of oncolytic viral therapy for various cancers.

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Meumann, Nadja, Christian Schmithals, Leroy Elenschneider, Tanja Hansen, Asha Balakrishnan, Qingluan Hu, Sebastian Hook et al. « Hepatocellular Carcinoma Is a Natural Target for Adeno-Associated Virus (AAV) 2 Vectors ». Cancers 14, n^o 2 (15 janvier 2022) : 427. http://dx.doi.org/10.3390/cancers14020427.

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Although therapeutic options are gradually improving, the overall prognosis for patients with hepatocellular carcinoma (HCC) is still poor. Gene therapy-based strategies are developed to complement the therapeutic armamentarium, both in early and late-stage disease. For efficient delivery of transgenes with antitumor activity, vectors demonstrating preferred tumor tropism are required. Here, we report on the natural tropism of adeno-associated virus (AAV) serotype 2 vectors for HCC. When applied intravenously in transgenic HCC mouse models, similar amounts of vectors were detected in the liver and liver tumor tissue. In contrast, transduction efficiency, as indicated by the level of transgene product, was moderate in the liver but was elevated up to 19-fold in mouse tumor tissue. Preferred transduction of HCC compared to hepatocytes was confirmed in precision-cut liver slices from human patient samples. Our mechanistic studies revealed that this preference is due to the improved intracellular processing of AAV2 vectors in HCC, resulting, for example, in nearly 4-fold more AAV vector episomes that serve as templates for gene transcription. Given this background, AAV2 vectors ought to be considered to strengthen current—or develop novel—strategies for treating HCC.

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