Journal articles: 'Invasive phenotype'

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Golmohammadi, Rahim, Mohammad Reza Mohajeri, Alireza Mosavi Jarrahi, Ali Reza Moslem, Akbar Pejhan, and Ali Gohari. "Histopathologic Characteristics of Invasive and Non-invasive Ductal Tumors have Relationship with Different Phenotypes of ER / PR Receptors in Breast Cancer Patients." Asian Pacific Journal of Cancer Biology 6, no. 3 (July 9, 2021): 181–85. http://dx.doi.org/10.31557/apjcb.2021.6.3.181-185.

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Objective: Contradictory reports have been published regarding the expression levels of the hormone receptors of estrogen and progesterone (ER / PR) and theirclinical importance in diagnosis of breast cancer. The aim of this study was to evaluate the relationship between pathological features of invasive and non-invasive ductal tumors by different ER / PR phenotypes. Methods: This descriptive-analytical study was performed on 74 specimens of breast cancer referred to Isfahan Hospitals for diagnosis between 2015 - 2018. After fixation of the specimens in formalin, tissue passage, cross section and H / E staining, the specimens were divided into two groups: non- invasive and Invasive ductal Carcinoma. After removing of mask, expression of different ER / PR phenotypes was performed using primary monoclonal antibody and immunohistochemically methods. Results: From 74 malignant specimens, 61 (82.4%) were in the category of invasive ductal tumors and 13 cases (17.6%) were in the category of non-invasive ductal tumors. Out of 73 patients with positive ER or PR phenotype 47 samples (63.5%) had ER + / PR +phenotypes, 6 samples had (8.1%) ER+ / PR –phenotype, 20 samples (27%) had ER- / PR + phenotype and only one sample (1.4%) had the ER- / PR- phenotype and was in the category of invasive ductal tumors. There was not detected ER- / PR- phenotype expression in non-invasive ductal tumor. Further analysis showed that there were not significant difference between ER / PR phenotype and tumor stage (p =0.36) or with tumor Grade (P=0.38), high age of menopause or post menopause (P> 0.05). Conclusion: Our data shows that expression of ER- / PR- phenotype only was detected in invasive ductal tumor. It is thought that the tumor type maybe affects the expression of different types of ER / PR hormone receptor phenotypes in breast cancer patients.

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Akeda, Yukihiro, Kenichi Nagayama, Koichiro Yamamoto, and Takeshi Honda. "Invasive Phenotype ofVibrio parahaemolyticus." Journal of Infectious Diseases 176, no. 3 (September 1997): 822–24. http://dx.doi.org/10.1086/517312.

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Márquez, A., H. J. Fino, M. Correa, P. Tonino, and L. Sosa. "Ultrastructure of Leiomyosarcoma Invasive Phenotype." Microscopy and Microanalysis 3, S2 (August 1997): 19–20. http://dx.doi.org/10.1017/s143192760000698x.

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Malignant tumors are known to have an heterogeneous cell population. Metastases are supposed to be formed by subpopulations with high metastatic capability. These metastatic cells constitute the so called invasive phenotype. In that order of ideas, metastases could be pathologically different from their parent tumors if the invasive phenotype had distinct morphological features. The similarities or differences between primary tumors and their metastases have not been adequately studied at the ultrastructural level. In this work we report an electron microscopic study of liver leiomyosarcoma metastases which shows alterations not described in primary tumors of that kind.Biopsies of liver metastases from a colon leiomyosarcoma were surgically obtained. Samples were processed with routine techniques for transmission electron microscopy and observed in a Hitachi H-500 electron microscope.Some alterations usually observed in primary leiomyosarcomas were seen. They were presence of myofilaments with focal densities, nuclear changes, swollen mitochondria, and abundance of rough endoplasmic reticulum (Fig. 1).

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Čermák, Vladimír, Aneta Škarková, Ladislav Merta, Veronika Kolomazníková, Veronika Palušová, Stjepan Uldrijan, Daniel Rösel, and Jan Brábek. "RNA-seq Characterization of Melanoma Phenotype Switch in 3D Collagen after p38 MAPK Inhibitor Treatment." Biomolecules 11, no. 3 (March 17, 2021): 449. http://dx.doi.org/10.3390/biom11030449.

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Melanoma phenotype plasticity underlies tumour dissemination and resistance to therapy, yet its regulation is incompletely understood. In vivo switching between a more differentiated, proliferative phenotype and a dedifferentiated, invasive phenotype is directed by the tumour microenvironment. We found that treatment of partially dedifferentiated, invasive A375M2 cells with two structurally unrelated p38 MAPK inhibitors, SB2021920 and BIRB796, induces a phenotype switch in 3D collagen, as documented by increased expression of melanocyte differentiation markers and a loss of invasive phenotype markers. The phenotype is accompanied by morphological change corresponding to amoeboid–mesenchymal transition. We performed RNA sequencing with an Illumina HiSeq platform to fully characterise transcriptome changes underlying the switch. Gene expression results obtained with RNA-seq were validated by comparing them with RT-qPCR. Transcriptomic data generated in the study will extend the present understanding of phenotype plasticity in melanoma and its contribution to invasion and metastasis.

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Shelley, Greg, Jinlu Dai, Jill M. Keller, and Evan T. Keller. "Pheno-SELEX: Engineering Anti-Metastatic Aptamers through Targeting the Invasive Phenotype Using Systemic Evolution of Ligands by Exponential Enrichment." Bioengineering 8, no. 12 (December 13, 2021): 212. http://dx.doi.org/10.3390/bioengineering8120212.

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Multiple methods (e.g., small molecules and antibodies) have been engineered to target specific proteins and signaling pathways in cancer. However, many mediators of the cancer phenotype are unknown and the ability to target these phenotypes would help mitigate cancer. Aptamers are small DNA or RNA molecules that are designed for therapeutic use. The design of aptamers to target cancers can be challenging. Accordingly, to engineer functionally anti-metastatic aptamers we used a modification of systemic evolution of ligands by exponential enrichment (SELEX) we call Pheno-SELEX to target a known phenotype of cancer metastasis, i.e., invasion. A highly invasive prostate cancer (PCa) cell line was established and used to identify aptamers that bound to it with high affinity as opposed to a less invasive variant to the cell line. The anti-invasive aptamer (AIA1) was found to inhibit in vitro invasion of the original highly invasive PCa cell line, as well as an additional PCa cell line and an osteosarcoma cell line. AIA1 also inhibited in vivo development of metastasis in both a PCa and osteosarcoma model of metastasis. These results indicate that Pheno-SELEX can be successfully used to identify aptamers without knowledge of underlying molecular targets. This study establishes a new paradigm for the identification of functional aptamers.

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van de Merbel, Arjanneke F., Onno van Hooij, Geertje van der Horst, Cindy C. M. van Rijt-van de Westerlo, Maaike H. van der Mark, Henry Cheung, Jan Kroon, et al. "The Identification of Small Molecule Inhibitors That Reduce Invasion and Metastasis of Aggressive Cancers." International Journal of Molecular Sciences 22, no. 4 (February 8, 2021): 1688. http://dx.doi.org/10.3390/ijms22041688.

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Transformed epithelial cells can activate programs of epithelial plasticity and switch from a sessile, epithelial phenotype to a motile, mesenchymal phenotype. This process is linked to the acquisition of an invasive phenotype and the formation of distant metastases. The development of compounds that block the acquisition of an invasive phenotype or revert the invasive mesenchymal phenotype into a more differentiated epithelial phenotype represent a promising anticancer strategy. In a high-throughput assay based on E-cadherin (re)induction and the inhibition of tumor cell invasion, 44,475 low molecular weight (LMW) compounds were screened. The screening resulted in the identification of candidate compounds from the PROAM02 class. Selected LMW compounds activated E-cadherin promoter activity and inhibited cancer cell invasion in multiple metastatic human cancer cell lines. The intraperitoneal administration of selected LMW compounds reduced the tumor burden in human prostate and breast cancer in vivo mouse models. Moreover, selected LMW compounds decreased the intra-bone growth of xenografted human prostate cancer cells. This study describes the identification of the PROAM02 class of small molecules that can be exploited to reduce cancer cell invasion and metastases. Further clinical evaluation of selected candidate inhibitors is warranted to address their safety, bioavailability and antitumor efficacy in the management of patients with aggressive cancers.

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Schuster, A., V. Neirinckx, E. Klein, P. V. Nazarov, A. Oudin, A. Muller, F. Azuaje, C. Herold-Mende, B. Klink, and S. P. Niclou. "P11.26 Genome-wide shRNA screen identifies candidate genes driving glioblastoma invasion." Neuro-Oncology 21, Supplement_3 (August 2019): iii48. http://dx.doi.org/10.1093/neuonc/noz126.172.

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Abstract BACKGROUND A major hallmark of glioblastoma (GBM) is its highly invasive capacity, contributing to its aggressive behaviour. Since invasive cells cannot be easily removed by surgery or irradiation, they are left behind and eventually result in lethal recurrence. Therefore, a better understanding of the invasion process and of the key molecular players underlying the invasive capacities of GBM may lead to the identification of new therapeutic targets for GBM patients. MATERIAL AND METHODS To identify candidate genes responsible for invasion, a genome-wide shRNA screen was performed in patient-derived GBM sphere cultures. The phenotype of the most promising candidate was validated in in vitro invasion assays, ex vivo brain slice cultures and in vivo orthotopic xenografts in mice. Gene knockdown in invasive GBM cell lines was compared with overexpression in non-invasive cells. RNA sequencing of knockdown cells, along with the generation of deletion constructs were applied to uncover the mechanisms regulating invasion. RESULTS Through a whole genome shRNA screen, a zinc-finger containing protein was identified as an invasion essential candidate gene. Knockdown of this gene confirmed a strong decrease in invasion capacity in two highly invasive GBM cell lines. In contrast, gene overexpression switched non-invasive GBM cells to an invasive phenotype. Deletion of either one or both zinc-finger motifs led to decreased invasion indicating that the two zinc-finger motifs are essential for regulating invasion. Mutation of the nuclear localisation signal resulted in retention of the protein in the cytoplasm and loss of the invasion phenotype demonstrating that the protein activity is required in the nucleus. Gene expression analyses revealed that invasion-related genes are significantly regulated by the candidate gene once it is localized in the nucleus. CONCLUSION We identified a zinc-finger containing protein as a novel driver of GBM invasion, presumably through a transcription factor activity resulting in the induction of an invasive transcriptional program. This protein and its downstream pathway may represent a novel promising target to overcome invasive capacities in GBM.

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Mukhopadhyay, Utpal K., Patrick Mooney, Lilly Jia, Robert Eves, Leda Raptis, and Alan S. Mak. "Doubles Game: Src-Stat3 versus p53-PTEN in Cellular Migration and Invasion." Molecular and Cellular Biology 30, no. 21 (August 23, 2010): 4980–95. http://dx.doi.org/10.1128/mcb.00004-10.

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ABSTRACT We have recently shown that Src induces the formation of podosomes and cell invasion by suppressing endogenous p53, while enhanced p53 strongly represses the Src-induced invasive phenotype. However, the mechanism by which Src and p53 play antagonistic roles in cell invasion is unknown. Here we show that the Stat3 oncogene is a required downstream effector of Src in inducing podosome structures and related invasive phenotypes. Stat3 promotes Src phenotypes through the suppression of p53 and the p53-inducible protein caldesmon, a known podosome antagonist. In contrast, enhanced p53 attenuates Stat3 function and Src-induced podosome formation by upregulating the tumor suppressor PTEN. PTEN, through the inactivation of Src/Stat3 function, also stabilizes the podosome-antagonizing p53/caldesmon axis, thereby further enhancing the anti-invasive potential of the cell. Furthermore, the protein phosphatase activity of PTEN plays a major role in the negative regulation of the Src/Stat3 pathway and represses podosome formation. Our data suggest that cellular invasiveness is dependent on the balance between two opposing forces: the proinvasive oncogenes Src-Stat3 and the anti-invasive tumor suppressors p53-PTEN.

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Gajić, Ina, Miloš Marković, Dušan Kekić, Sunčica Popović, Vera Mijač, Lazar Ranin, and Nataša Opavski. "Serotypes and antimicrobial susceptibility of invasive 'Streptococcus pneumoniae' isolated in Serbia in 2012-2013." Medicinska istrazivanja 50, no. 2 (2016): 49–53. http://dx.doi.org/10.5937/medist1602049g.

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The aim of this study was to: determine susceptibility patterns of invasive Streptococcus pneumoniae to antimicrobial agents, evaluate macrolide resistance phenotypes and genotypes and identify capsular serotypes among invasive isolates of S. pneumoniae circulating in Serbia. The total of 85 invasive pneumococcal strains, collected during 2012 and 2013, were sent from regional laboratories to the National Reference Laboratory. Susceptibility testing was performed by disk diffusion and E test, while phenotypes and genotypes of macrolide resistant strains were determined by double-test and PCR, respectively. Serotyping was performed by Quelling reaction. The overall penicillin and erythromycin non-susceptibility rates were 14.12% and 28.23%, respectively. Resistance rates were significantly higher in children than in adults and (p<0,01). Co-resistance to penicillin and erythromycin was detected in 7.06% strains. Resistance rates to tetracycline and chloramphenicol were 29.41% and 15.29%, respectively. The rate of multi resistance was 27.06%. cMLS phenotype was detected in 62.5% of all macrolide resistant isolates, while 37.5% expressed M phenotype. All 15 isolates with cMLS phenotype harbored ermB gene and all M isolates harbored mefA. The most common resistant serotypes were 3, 9A and 23F. This study revealed that penicillin and macrolide resistance among invasive pneumococcal isolates is high. Obtained results emphasize the need for continuous monitoring of invasive pneumococcal disease in Serbia.

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Akeda, Yukihiro, Toshio Kodama, Takashige Kashimoto, Vlademir Cantarelli, Yasuhiko Horiguchi, Kenichi Nagayama, Tetsuya Iida, and Takeshi Honda. "Dominant-Negative Rho, Rac, and Cdc42 Facilitate the Invasion Process of Vibrio parahaemolyticus into Caco-2 Cells." Infection and Immunity 70, no. 2 (February 2002): 970–73. http://dx.doi.org/10.1128/iai.70.2.970-973.2002.

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ABSTRACT To clarify the invasive process of Vibrio parahaemolyticus, an invasion assay was performed using cells expressing dominant negative small GTPases of the Rho family. This assay showed that the dominant negative host phenotype facilitates bacterial invasion, suggesting that the mechanism of V. parahaemolyticus invasion differs from that reported for other invasive bacteria.

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Wang, Zihao, Xiaopeng Guo, Wenze Wang, Lu Gao, Xinjie Bao, Ming Feng, Wei Lian, Huijuan Zhu, and Bing Xing. "UPLC-MS/MS-based Lipidomic Profiles Revealed Aberrant Lipids Associated with Invasiveness of Silent Corticotroph Adenoma." Journal of Clinical Endocrinology & Metabolism 106, no. 1 (August 8, 2020): e273-e287. http://dx.doi.org/10.1210/clinem/dgaa708.

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Abstract Context The accumulation of aberrant lipids and abnormal lipid metabolism in silent corticotroph adenomas (SCAs) could contribute to changes in clinical phenotypes, especially sphenoid sinus invasion. Objective To systematically investigate lipidomic and transcriptomic alterations associated with invasiveness and their potential molecular mechanisms in SCAs and to provide candidate biomarkers for predicting invasiveness and novel treatment options for invasive SCAs by targeting lipids. Methods Fifty-four SCAs (34 invasive/20 noninvasive) were subjected to lipidomic analysis based on ultraperformance liquid chromatography mass spectrometry, and 42 clinically nonfunctioning pituitary adenomas (23 invasive/19 noninvasive) were subjected to transcriptomic analysis. Differential analysis was performed to determine differential lipids and genes between invasive and noninvasive tumors. A functionally connected network was constructed with the molecular pathways as cores. Multiple machine learning methods were applied to identify the most critical lipids, which were further used to construct a lipidomic signature to predict invasive SCAs by multivariate logistic regression, and its performance was evaluated by receiver operating characteristic analysis. Results Twenty-eight differential lipids were identified, and a functionally connected network was constructed with 2 lipids, 17 genes, and 4 molecular pathways. Connectivity Map (CMap) analysis further revealed 32 potential drugs targeting 4 genes and related pathways. The 4 most critical lipids were identified as risk factors contributing to the invasive phenotype. A lipidomic signature was constructed and showed excellent performance in discriminating invasive and noninvasive SCAs. Conclusions The lipidomic signature could serve as a promising predictor for the invasive SCA phenotype and provide potential therapeutic targets for SCAs.

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Villar, C. C., H. Kashleva, A. P. Mitchell, and A. Dongari-Bagtzoglou. "Invasive Phenotype of Candida albicans Affects the Host Proinflammatory Response to Infection." Infection and Immunity 73, no. 8 (August 2005): 4588–95. http://dx.doi.org/10.1128/iai.73.8.4588-4595.2005.

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ABSTRACT Candida albicans is a major opportunistic pathogen in immunocompromised patients. Production of proinflammatory cytokines by host cells in response to C. albicans plays a critical role in the activation of immune cells and final clearance of the organism. Invasion of host cells and tissues is considered one of the virulence attributes of this organism. The purpose of this study was to investigate whether the ability of C. albicans to invade host cells and tissues affects the proinflammatory cytokine responses by epithelial and endothelial cells. In this study we used the invasion-deficient RIM101 gene knockout strain DAY25, the highly invasive strain SC5314, and highly invasive RIM101-complemented strain DAY44 to compare the proinflammatory cytokine responses by oral epithelial or endothelial cells. Using a high-throughput approach, we found both qualitative and quantitative differences in the overall inflammatory responses to C. albicans strains with different invasive potentials. Overall, the highly invasive strains triggered higher levels of proinflammatory cytokines in host cells than the invasion-deficient mutant triggered. Significant differences compared to the attenuated mutant were noted in interleukin-1α (IL-1α), IL-6, IL-8, and tumor necrosis factor alpha in epithelial cells and in IL-6, growth-related oncogene, IL-8, monocyte chemoattractant protein 1 (MCP-1), MCP-2, and granulocyte colony-stimulating factor in endothelial cells. Our results indicate that invasion of host cells and tissues by C. albicans enhances the host proinflammatory response to infection.

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Schuster, Anne, Virginie Neirinckx, Eliane Klein, Petr V. Nazarov, Anais Oudin, Arnaud Muller, Fransisco Azuaje, Christel Herold-Mende, Barbara Klink, and Simone Niclou. "ANGI-02. GENOME-WIDE shRNA SCREEN IDENTIFIES CANDIDATE GENES DRIVING GLIOBLASTOMA INVASION." Neuro-Oncology 21, Supplement_6 (November 2019): vi30. http://dx.doi.org/10.1093/neuonc/noz175.113.

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Abstract BACKGROUND A major hallmark of glioblastoma (GBM) is its invasive capacity, contributing to its aggressive behaviour. Invasive cells cannot be easily removed by surgery or irradiation and eventually result in lethal recurrence. A better understanding of the invasion process and the key molecular players underlying the invasive potential of GBM may lead to the identification of new therapeutic targets for GBM patients. MATERIAL AND METHODS To identify candidate genes responsible for invasion, a genome-wide shRNA screen was performed in patient-derived GBM cultures. The most promising candidate was validated in in vitro invasion assays, ex vivo brain slice cultures and in vivo orthotopic xenografts in mice. Gene knockdown in invasive GBM cells was compared with overexpression in non-invasive cells. RNAseq of knockdown cells, along with the generation of deletion constructs were applied to uncover the mechanisms regulating invasion. RESULTS A zinc-finger domain containing protein was identified as an invasion essential candidate gene. Knockdown of this gene confirmed a strong impact on invasion in highly invasive GBM cells. In contrast, gene overexpression switched non-invasive GBM cells to an invasive phenotype. Deletion of one or both zinc-finger motifs decreased invasion indicating that both are essential for regulating invasion. Mutation of the nuclear localisation signal resulted in retention of the protein in the cytoplasm and loss of the invasion phenotype demonstrating that the protein activity is required in the nucleus. Gene expression analyses revealed that invasion-related genes are significantly regulated by the candidate gene once it is localized in the nucleus. CONCLUSION We identified a zinc-finger containing protein as a novel driver of GBM invasion, presumably through transcription factor activity resulting in the induction of an invasive transcriptional program. This protein and its downstream pathway may represent novel promising targets to overcome invasive capacities in GBM.

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Essay, Patrick, Jarrod Mosier, and Vignesh Subbian. "Rule-Based Cohort Definitions for Acute Respiratory Failure: Electronic Phenotyping Algorithm." JMIR Medical Informatics 8, no. 4 (April 15, 2020): e18402. http://dx.doi.org/10.2196/18402.

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Background Acute respiratory failure is generally treated with invasive mechanical ventilation or noninvasive respiratory support strategies. The efficacies of the various strategies are not fully understood. There is a need for accurate therapy-based phenotyping for secondary analyses of electronic health record data to answer research questions regarding respiratory management and outcomes with each strategy. Objective The objective of this study was to address knowledge gaps related to ventilation therapy strategies across diverse patient populations by developing an algorithm for accurate identification of patients with acute respiratory failure. To accomplish this objective, our goal was to develop rule-based computable phenotypes for patients with acute respiratory failure using remotely monitored intensive care unit (tele-ICU) data. This approach permits analyses by ventilation strategy across broad patient populations of interest with the ability to sub-phenotype as research questions require. Methods Tele-ICU data from ≥200 hospitals were used to create a rule-based algorithm for phenotyping patients with acute respiratory failure, defined as an adult patient requiring invasive mechanical ventilation or a noninvasive strategy. The dataset spans a wide range of hospitals and ICU types across all US regions. Structured clinical data, including ventilation therapy start and stop times, medication records, and nurse and respiratory therapy charts, were used to define clinical phenotypes. All adult patients of any diagnoses with record of ventilation therapy were included. Patients were categorized by ventilation type, and analysis of event sequences using record timestamps defined each phenotype. Manual validation was performed on 5% of patients in each phenotype. Results We developed 7 phenotypes: (0) invasive mechanical ventilation, (1) noninvasive positive-pressure ventilation, (2) high-flow nasal insufflation, (3) noninvasive positive-pressure ventilation subsequently requiring intubation, (4) high-flow nasal insufflation subsequently requiring intubation, (5) invasive mechanical ventilation with extubation to noninvasive positive-pressure ventilation, and (6) invasive mechanical ventilation with extubation to high-flow nasal insufflation. A total of 27,734 patients met our phenotype criteria and were categorized into these ventilation subgroups. Manual validation of a random selection of 5% of records from each phenotype resulted in a total accuracy of 88% and a precision and recall of 0.8789 and 0.8785, respectively, across all phenotypes. Individual phenotype validation showed that the algorithm categorizes patients particularly well but has challenges with patients that require ≥2 management strategies. Conclusions Our proposed computable phenotyping algorithm for patients with acute respiratory failure effectively identifies patients for therapy-focused research regardless of admission diagnosis or comorbidities and allows for management strategy comparisons across populations of interest.

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Tuma, Rabiya S. "Src Inhibitor Targets Invasive Phenotype of Cancers." Oncology Times 29, Supplement (August 2007): 12–13. http://dx.doi.org/10.1097/01.cot.0000288487.20631.5f.

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Tuma, Rabiya S. "Src inhibitor targets invasive phenotype of cancers." Oncology Times UK 4, no. 9 (September 2007): 20. http://dx.doi.org/10.1097/01434893-200709000-00018.

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Gajic, Ina, Natasa Opavski, Vera Mijac, and L. Ranin. "Macrolide-resistant phenotypes of invasive streptococcus pneumoniae isolates in Serbia." Archives of Biological Sciences 64, no. 4 (2012): 1377–82. http://dx.doi.org/10.2298/abs1204377g.

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Macrolide resistance in Streptococcus pneumoniae has emerged as an important worldwide problem over the past decade. The aim of this study was to investigate macrolide-resistant phenotypes and the antimicrobial susceptibility patterns of invasive pneumococci in Serbia. A total of 68 invasive pneumococcal strains, collected from 2009 to 2011, were sent from regional laboratories to the National Reference Laboratory. Susceptibility testing was performed using the VITEK2 system and phenotypes were determined by triple-test. Overall penicillin and erythromycin nonsusceptibility rates were 26% and 43%, respectively. Resistance rates were higher in children than in adults. Co-resistance to penicillin and erythromycin was detected in 18% strains. Resistance rates to the third generation of cephalosporins, TMP-SXT and tetracycline were 16%, 37% and 29%, respectively. All isolates were fully susceptible to vancomycin, linezolid, fluoroquinolones, telithromycin and rifampicin. Twenty-two isolates (79%) an expressed macrolide-lincosamide-streptogramin B (MLSB) resistance phenotype and M phenotype was found in 21% of macrolide resistant strains.

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Wu, Tony James. "Identifying mechanisms of macrophage-induced metastasis in pancreatic ductal adenocarcinoma." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e15705-e15705. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e15705.

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e15705 Background: Pancreatic ductal adenocarcinoma (PDAC) is a lethal, incurable disease. Macrophages are one of the most abundant, multifunctional immune cell populations in the tumor microenvironment and a major component of the immune infiltrate in many solid tumors. Methods: Employing a multi-omics approach, PDAC cell lines and primary macrophages were CTAP (cell-type specific labelling using amino acid precursors)-labelled and admixed together for a prolonged period of time. To identify cell-of-origin of novel RNA and proteins, these mixed co-cultures were FACS sorted for downstream RNA-sequencing analysis or harvested in bulk for downstream proteome and secretome analysis. Results: Here, we provide new insight into the dichotomous relationship between epithelial and mesenchymal phenotypes of PDAC cells in 3D culture. We report the ability of PDAC mesenchymal cells to form vascular mimicry-like structures in a 3D in vitro assay of invasion. Additionally, we demonstrate that macrophages have the ability to impart a pro-invasive phenotype to PDAC cells when co-cultured in 3D, regardless of EMT (epithelial-to-mesenchymal transition) status. Preliminary integration of cell culture transcriptomes with CTAP-TMT proteomes and secretomes implicates several key epithelial- and macrophage-derived signalling molecules as principal instructing signals for mediating the observed pro-invasive phenotype. Conclusions: Blockade of these signalling molecules or their receptors disrupted the crosstalk between PDAC cells and macrophages within the tumor microenvironment and impaired the ability of macrophages to induce a pro-invasive phenotype to PDAC cells.

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Khan, A., Y. E. Tovar, C. Rodriguez, A. L. Huerta, B. Rajabi, M. N. Hakim, and Z. D. Mulla. "Incidence of triple negative breast cancer phenotype in a predominantly Hispanic cohort." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): e22188-e22188. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e22188.

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e22188 Background: In daily oncology practice, triple-negative invasive breast cancer is defined by negative immunohistochemistry for ER, PR and HER-2. Patients with this phenotype experience poor prognosis due to limited treatment options and intrinsic tumor biology. In a population-based case-control study, the Carolina Breast Cancer Study (Carey et al, JCO, 2004: suppl; abstr 9510), the triple-negative phenotype in African-American women represented 33.9% of the tumors. We aimed to identify the incidence of triple-negative invasive breast cancer in a group of women living in a predominantly Hispanic population on the Texas- Mexico border. Methods: We collected retrospective data for all invasive breast cases diagnosed between January 2005 and December 2008 at our affiliated county hospital. Clinical and pathological features were summarized. ER, PR and HER-2 was performed by immunohistochemistry. Results: 309 patients with invasive breast cancer were identified. 23.9% (74 patients) of all breast cancer patients were triple-negative. 70 of the 74 subjects (94.6%) were Hispanic. There was equal distribution of patients over and under the age of 50. Histologically all cases were invasive ductal carcinoma. The vast majority had grade 3 tumors (82%) with a high Ki-67 proliferative index (97%). Lymphovascular invasion was present in 38 patients (51.4%). Distant metastases at diagnosis was found in 4 patients (5.4%). Conclusions: In our population-based study the proportion of triple-negative invasive breast cancer phenotype was not as high as in the Carolina Breast Cancer Study, but does reflect that a quarter of the patients with invasive breast cancer in this growing Hispanic population may carry this phenotype. The triple-negative phenotype was strongly associated with high tumor grade and proliferative index. No significant financial relationships to disclose.

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Zhou, Hong Y., Yuen L. Pon, and Alice S. T. Wong. "Synergistic Effects of Epidermal Growth Factor and Hepatocyte Growth Factor on Human Ovarian Cancer Cell Invasion and Migration: Role of Extracellular Signal-Regulated Kinase 1/2 and p38 Mitogen-Activated Protein Kinase." Endocrinology 148, no. 11 (November 1, 2007): 5195–208. http://dx.doi.org/10.1210/en.2007-0361.

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Ovarian cancer is the primary cause of death from gynecological malignancies with a poor prognosis characterized by widespread peritoneal dissemination. However, mechanisms of invasion and metastasis in ovarian cancer remain poorly understood. Epidermal growth factor (EGF) and hepatocyte growth factor (HGF) are often both overexpressed and contribute to the growth of ovarian cancer by activating autocrine pathways. In the present study, we investigated the mechanisms of invasive activity of EGF, HGF, and their synergistic effects in human ovarian cancer cells. Here our data suggest that EGF and HGF may use unique and overlapping signaling cascades leading to the invasive phenotype. We revealed that HGF-mediated cell migration and invasion required the coordinate activation of the phosphatidylinositol 3-kinase/Akt and extracellular signal-regulated kinase 1/2. Although EGF-dependent invasive phenotype appeared to have similar requirements for phosphatidylinositol 3-kinase, this growth factor used the alternative p38 MAPK pathway for cell invasion. A significant role of p38 MAPK was further supported by the observation that expression of dominant negative p38 MAPK likewise inhibited EGF-dependent invasiveness and cell motility. We also showed that EGF cooperated with HGF to promote a highly invasive phenotype via the increased secretion of matrix metalloproteinase (MMP)-9. The coincident induction of MMP-9 was functionally significant because inclusion of MMP-9 inhibitor or an anti-MMP-9 neutralizing antibody abolished EGF- and HGF-induced cellular invasion. These findings provide insights into the mechanism of the malignant progression of ovarian cancer.

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Gandalovičová, Aneta, Anna-Marie Šůchová, Vladimír Čermák, Ladislav Merta, Daniel Rösel, and Jan Brábek. "Sustained Inflammatory Signalling through Stat1/Stat2/IRF9 Is Associated with Amoeboid Phenotype of Melanoma Cells." Cancers 12, no. 9 (August 28, 2020): 2450. http://dx.doi.org/10.3390/cancers12092450.

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The invasive behaviour of cancer cells underlies metastatic dissemination; however, due to the large plasticity of invasion modes, it is challenging to target. It is now widely accepted that various secreted cytokines modulate the tumour microenvironment and pro-inflammatory signalling can promote tumour progression. Here, we report that cells after mesenchymal–amoeboid transition show the increased expression of genes associated with the type I interferon response. Moreover, the sustained activation of type I interferon signalling in response to IFNβ mediated by the Stat1/Stat2/IRF9 complex enhances the round amoeboid phenotype in melanoma cells, whereas its downregulation by various approaches promotes the mesenchymal invasive phenotype. Overall, we demonstrate that interferon signalling is associated with the amoeboid phenotype of cancer cells and suggest a novel role of IFNβ in promoting cancer invasion plasticity, aside from its known role as a tumour suppressor.

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Aoki, Tomoko, Naoshi Nishida, and Masatoshi Kudo. "Clinical Significance of the Duality of Wnt/β-Catenin Signaling in Human Hepatocellular Carcinoma." Cancers 14, no. 2 (January 17, 2022): 444. http://dx.doi.org/10.3390/cancers14020444.

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Combination therapy with immune checkpoint inhibitors (ICIs) and vascular endothelial growth factor inhibitors has been approved as a first-line treatment for unresectable hepatocellular carcinoma (HCC), indicating a critical role of ICIs in the treatment of HCC. However, 20% of patients do not respond effectively to ICIs; mutations in the activation of the Wnt/β-catenin pathway are known to contribute to primary resistance to ICIs. From this point of view, non-invasive detection of Wnt/β-catenin activation should be informative for the management of advanced HCC. Wnt/β-catenin mutations in HCC have a dual aspect, which results in two distinct tumor phenotypes. HCC with minimal vascular invasion, metastasis, and good prognosis is named the “Jekyll phenotype”, while the poorly differentiated HCC subset with frequent vascular invasion and metastasis, cancer stem cell features, and high serum Alpha fetoprotein levels, is named the “Hyde phenotype”. To differentiate these two HCC phenotypes, a combination of the hepatobiliary phase of gadolinium-ethoxybenzyl-diethylenetriamine (Gd-EOB-DTPA)-enhanced magnetic resonance imaging and fluoro-2-deoxy-D-glucose-PET/CT may be useful. The former is applicable for the detection of the Jekyll phenotype, as nodules present higher enhancement on the hepatobiliary phase, while the latter is likely to be informative for the detection of the Hyde phenotype by showing an increased glucose uptake.

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Desprez, Pierre-Yves, Claudia Qiao Lin, Nicole Thomasset, Carolyn J. Sympson, Mina J. Bissell, and Judith Campisi. "A Novel Pathway for Mammary Epithelial Cell Invasion Induced by the Helix-Loop-Helix Protein Id-1." Molecular and Cellular Biology 18, no. 8 (August 1, 1998): 4577–88. http://dx.doi.org/10.1128/mcb.18.8.4577.

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ABSTRACT Mammary epithelial cells undergo changes in growth, invasion, and differentiation throughout much of adulthood, and most strikingly during pregnancy, lactation, and involution. Although the pathways of milk protein expression are being elucidated, little is known, at a molecular level, about control of mammary epithelial cell phenotypes during normal tissue morphogenesis and evolution of aggressive breast cancer. We developed a murine mammary epithelial cell line, SCp2, that arrests growth and functionally differentiates in response to a basement membrane and lactogenic hormones. In these cells, expression of Id-1, an inhibitor of basic helix-loop-helix transcription factors, declines prior to differentiation, and constitutive Id-1 expression blocks differentiation. Here, we show that SCp2 cells that constitutively express Id-1 slowly invade the basement membrane but remain anchorage dependent for growth and do not form tumors in nude mice. Cells expressing Id-1 secreted a ∼120-kDa gelatinase. From inhibitor studies, this gelatinase appeared to be a metalloproteinase, and it was the only metalloproteinase detectable in conditioned medium from these cells. A nontoxic inhibitor diminished the activity of this metalloproteinase in vitro and repressed the invasive phenotype of Id-1-expressing cells in culture. The implications of these findings for normal mammary-gland development and human breast cancer were investigated. A gelatinase of ∼120 kDa was expressed by the mammary gland during involution, a time when Id-1 expression is high and there is extensive tissue remodeling. Moreover, high levels of Id-1 expression and the activity of a ∼120-kDa gelatinase correlated with a less-differentiated and more-aggressive phenotype in human breast cancer cells. We suggest that Id-1 controls invasion by normal and neoplastic mammary epithelial cells, primarily through induction of a ∼120-kDa gelatinase. This Id-1-regulated invasive phenotype could contribute to involution of the mammary gland and possibly to the development of invasive breast cancer.

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Yiu, Gary K., Aura Kaunisto, Y. Rebecca Chin, and Alex Toker. "NFAT promotes carcinoma invasive migration through glypican-6." Biochemical Journal 440, no. 1 (October 27, 2011): 157–66. http://dx.doi.org/10.1042/bj20110530.

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Invasive migration of carcinoma cells is a prerequisite for the metastatic dissemination of solid tumours. Numerous mechanisms control the ability of cancer cells to acquire a motile and invasive phenotype, and subsequently degrade and invade the basement membrane. Several genes that are up-regulated in breast carcinoma are responsible for mediating the metastatic cascade. Recent studies have revealed that the NFAT (nuclear factor of activated T-cells) is a transcription factor that is highly expressed in aggressive breast cancer cells and tissues, and mediates invasion through transcriptional induction of pro-invasion and migration genes. In the present paper we demonstrate that NFAT promotes breast carcinoma invasion through induction of GPC (glypican) 6, a cell-surface glycoprotein. NFAT transcriptionally regulates GPC6 induction in breast cancer cells and binds to three regulatory elements in the GPC6 proximal promoter. Expression of GPC6 in response to NFAT signalling promotes invasive migration, whereas GPC6 silencing with shRNA (small-hairpin RNA) potently blocks this phenotype. The mechanism by which GPC6 promotes invasive migration involves inhibition of canonical β-catenin and Wnt signalling, and up-regulation of non-canonical Wnt5A signalling leading to the activation of JNK (c-Jun N-terminal kinase) and p38 MAPK (mitogen-activated protein kinase). Thus GPC6 is a novel NFAT target gene in breast cancer cells that promotes invasive migration through Wnt5A signalling.

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Zucali, Paolo Andrea, Piergiuseppe Colombo, Camilla De Carlo, Laura Giordano, Rodolfo Hurle, Massimo Lazzeri, Grazia Maria Elefante, et al. "The neural phenotype in invasive urothelial carcinoma patients: Alternative score detection and prognostic implication." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e17037-e17037. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e17037.

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e17037 Background: Recent molecular subtyping studies (NGS) identified a subset (5-15%) of muscle invasive urothelial carcinoma (MIBC) with transcriptomic patterns consistent with neuroendocrine (NE) differentiation in the absence of NE histology (NE-like), representing a potentially high risk subgroup of carcinoma which may require a different treatment strategy. We recently set an alternative immuno-phenotypical score (Piescore), to discriminate Luminal from Basal from Neural carcinoma. Aim of this study was to test the ability of Piescore in identifying NE-like cases in a mono-institutional cohort of patients treated with trans-urethral resection and radical cystectomy (RC) and to correlate them with clinical outcomes. Methods: Transurethral resection specimens harbored foci of HG pT2 (MIBC) UC from 116 pts who subsequently underwent RC have been submitted for immunohistochemical analysis, using relevant gene-expression-based markers for Basal type (CD44, CK5/6) and Luminal type (CK20 and pPARg). Piescore divided Basal and Luminal types when at least 3 of the 4 markers were consistent with a specific phenotype; Mixed if two luminal and two basal markers were present simultaneously; NE-like when all four markers were negative. Results: Overall, the Piescore identified Basal phenotypes in 49 patients (42,2%), Luminal in 38 (32,7%), and Mixed in 9 (7,8%). No expression was identified in 20 patients (17,2%): 7 cases with morphological NE differentiation and 13 cases with classical urothelial histology, all consistent with NE-like phenotype. Interestingly, in 10/13 patients the NE-like phenotype was only documented in the muscle invasive component of the tumor whereas in the non-invasive component they retained Luminal phenotype in 9 cases and Basal in one. With a median follow up of 188 months, the pathological stage of disease (pT2 versus ≥pT3 and/or N+) and the tumor vascular invasion (absent versus present) resulted prognostic (Stage: 5-years DFS rate 65% versus 30%, p = 0.038; 5-years OS rate 69% versus 32%, p = 0.017) (vascular invasion: 5-years DFS rate 47% versus 24%, p = 0.020; 5-years OS rate 54% versus 21%, p < 0.001) in all population. No statistically significant differences in terms of pathological stage of disease, vascular invasion, DFS, and OS were observed in NE-like cases compared with non-NE-like cases. Conclusions: The NE-like urothelial carcinoma identified by Piescore immunophenotyping (CD44, CK5/6, CK20 and pPARg) did not show any statistically significant association with worse prognosis.

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Fritah, Asmaà, Cécile Saucier, Olivier De Wever, Marc Bracke, Ivan Bièche, Rosette Lidereau, Christian Gespach, Sylvain Drouot, Gérard Redeuilh, and Michèle Sabbah. "Role of WISP-2/CCN5 in the Maintenance of a Differentiated and Noninvasive Phenotype in Human Breast Cancer Cells." Molecular and Cellular Biology 28, no. 3 (December 18, 2007): 1114–23. http://dx.doi.org/10.1128/mcb.01335-07.

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ABSTRACT WISP-2/CCN5 is an estrogen-regulated member of the “connective tissue growth factor/cysteine-rich 61/nephroblastoma overexpressed” (CCN) family of the cell growth and differentiation regulators. The WISP-2/CCN5 mRNA transcript is undetectable in normal human mammary cells, as well as in highly aggressive breast cancer cell lines, in contrast with its higher level in the breast cancer cell lines characterized by a more differentiated phenotype. We report here that knockdown of WISP-2/CCN5 by RNA interference in estrogen receptor alpha (ERα)-positive MCF-7 breast cancer cells induced an estradiol-independent growth linked to a loss of ERα expression and promoted epithelial-to-mesenchymal transdifferentiation. In contrast, forced expression of WISP-2/CCN5 directed MCF-7 cells toward a more differentiated phenotype. When introduced into the poorly differentiated, estrogen-independent, and invasive MDA-MB-231 breast cancer cells, WISP-2/CCN5 was able to reduce their proliferative and invasive phenotypes. In a series of ERα-positive tumor biopsies, we found a positive correlation between the expression of WISP-2/CCN5 and ID2, a transcriptional regulator of differentiation in normal and transformed breast cells. We propose that WISP-2/CCN5 is an important regulator involved in the maintenance of a differentiated phenotype in breast tumor epithelial cells and may play a role in tumor cell invasion and metastasis.

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da Fonseca, Leonardo Marques, Danilo Macedo Calvalhan, Jose Osvaldo Previato, Lucia Mendonça Previato, and Leonardo Freire-de-Lima. "Resistance to paclitaxel induces glycophenotype changes and mesenchymal-to-epithelial transition activation in the human prostate cancer cell line PC-3." Tumor Biology 42, no. 9 (September 2020): 101042832095750. http://dx.doi.org/10.1177/1010428320957506.

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The development of the multidrug resistance phenotype is one of the major challenges faced in the treatment of cancer. The multidrug resistance phenotype is characterized by cross-resistance to drugs with different chemical structures and mechanisms of action. In this work, we hypothesized that the acquisition of resistance in cancer is accompanied by activation of the epithelial-to-mesenchymal transition process, where the tumor cell acquires a more mobile and invasive phenotype; a fundamental step in tumor progression and in promoting the invasion of other organs and tissues. In addition, it is known that atypical glycosylations are characteristic of tumor cells, being used as biomarkers. We believe that the acquisition of the multidrug resistance phenotype and the activation of epithelial-to-mesenchymal transition provoke alterations in the cell glycophenotype, which can be used as glycomarkers for chemoresistance and epithelial-to-mesenchymal transition processes. Herein, we induced the multidrug resistance phenotype in the PC-3 human prostate adenocarcinoma line through the continuous treatment with the drug paclitaxel. Our results showed that the induced cell multidrug resistance phenotype (1) acquired a mixed profile between epithelial and mesenchymal phenotypes and (2) modified the glycophenotype, showing an increase in the level of sialylation and in the number of branched glycans. Both mechanisms are described as indicators of poor prognosis.

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Ciolczyk-Wierzbicka, Dorota, Marek Bodzioch, Dorota Gil, Danuta Zmudzinska, Aldona Dembinska-Kiec, and Piotr Laidler. "Expression of Fucosyltransferases Contributes to Melanoma Invasive Phenotype." Medicinal Chemistry 3, no. 5 (September 1, 2007): 418–24. http://dx.doi.org/10.2174/157340607781745401.

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Ingram, Jennifer L., Molly J. Huggins, Tony D. Church, Yuejuan Li, Dave C. Francisco, Simone Degan, Rafael Firszt, et al. "Airway Fibroblasts in Asthma Manifest an Invasive Phenotype." American Journal of Respiratory and Critical Care Medicine 183, no. 12 (June 15, 2011): 1625–32. http://dx.doi.org/10.1164/rccm.201009-1452oc.

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Visscher, D. W., F. H. Sarkar, W. Sakr, and J. Crissman. "Immunohistologic analysis of invasive phenotype in breast carcinoma." Pathology - Research and Practice 189, no. 8 (September 1993): 867–72. http://dx.doi.org/10.1016/s0344-0338(11)81096-4.

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Merikallio, Heta, Taina Turpeenniemi-Hujanen, Paavo Pääkkö, Riitta Mäkitaro, Kaarteenaho Riitta, Sirpa Salo, Tuula Salo, Terttu Harju, and Ylermi Soini. "Snail promotes an invasive phenotype in lung carcinoma." Respiratory Research 13, no. 1 (2012): 104. http://dx.doi.org/10.1186/1465-9921-13-104.

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Tse, J. M., G. Cheng, J. A. Tyrrell, S. A. Wilcox-Adelman, Y. Boucher, R. K. Jain, and L. L. Munn. "Mechanical compression drives cancer cells toward invasive phenotype." Proceedings of the National Academy of Sciences 109, no. 3 (December 27, 2011): 911–16. http://dx.doi.org/10.1073/pnas.1118910109.

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Scott, LJ, NW Clarke, MS Sharrard, NJR George, and SH Lang. "Invasive phenotype of primary human prostatic epithelial cells." Prostate Cancer and Prostatic Diseases 3, S1 (December 2000): S8. http://dx.doi.org/10.1038/sj.pcan.4500432.

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Ishihara, Rei, Tsukasa Oda, Yuki Murakami, Ikuko Matsumura, Saki Watanabe, Yuta Asao, Yuta Masuda, et al. "Myeloma Microenvironmental TIMP1 Induces the Invasive Phenotype in Fibroblasts to Modulate Disease Progression." International Journal of Molecular Sciences 24, no. 3 (January 22, 2023): 2216. http://dx.doi.org/10.3390/ijms24032216.

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Tissue inhibitors of metalloproteinases (TIMPs) are endogenous matrix metalloproteinase inhibitors. TIMP1 is produced by cancer cells and has pleiotropic activities. However, its role and source in multiple myeloma (MM) are unclear. Here, we evaluated TIMP1 protein and mRNA levels in bone marrow (BM) plasma cells and assessed the effects of TIMP1 expression on fibroblast invasive capacity using three-dimensional spheroid cell invasion assays. TIMP1 mRNA and protein levels were elevated when patients progressed from monoclonal gammopathy of undetermined significance or smouldering myeloma to MM. Furthermore, TIMP1 levels decreased at complete response and TIMP1 protein levels increased with higher international staging. TIMP1 mRNA levels were markedly higher in extramedullary plasmacytoma and MM with t(4;14). Overall survival and post-progression survival were significantly lower in MM patients with high TIMP1 protein. Recombinant TIMP1 did not directly affect MM cells but enhanced the invasive capacity of fibroblasts; this effect was suppressed by treatment with anti-TIMP1 antibodies. Fibroblasts supported myeloma cell invasion and expansion in extracellular matrix. Overall, these results suggested that MM-derived TIMP1 induces the invasive phenotype in fibroblasts and is involved in disease progression. Further studies are required to elucidate the specific roles of TIMP1 in MM and facilitate the development of novel therapies targeting the TIMP1 pathway.

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Hiscox, Stephen, L. Morgan, Tim Green, and Robert I. Nicholson. "Src as a therapeutic target in anti-hormone/anti-growth factor-resistant breast cancer." Endocrine-Related Cancer 13, Supplement_1 (December 2006): S53—S59. http://dx.doi.org/10.1677/erc.1.01297.

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Endocrine therapy is the treatment of choice in hormone receptor-positive breast cancer. However, the effectiveness of anti-hormone drugs, such as tamoxifen, is limited because of the development of resistance, ultimately leading to disease progression and patient mortality. Using in vitro cell models of anti-hormone resistance, we have previously demonstrated that altered growth factor signalling contributes to an endocrine insensitive phenotype. Significantly, our recent studies have revealed that the acquisition of endocrine resistance in breast cancer is accompanied by a greatly enhanced migratory and invasive phenotype. Furthermore, therapeutic intervention using anti-growth factor monotherapies, despite an initial growth suppressive phase, again results in the development of a resistant state and a further augmentation of their invasive phenotype. Using the dual specific Src/Abl kinase inhibitor, AZD0530, we have highlighted a central role for Src kinase in promoting the invasive phenotype that accompanies both anti-hormone and anti-growth factor resistance. Importantly, the use of Src inhibitors in combination with anti-growth factor therapies appears to be additive, producing a marked inhibitory effect on cell growth, migration and invasion and ultimately prevents the emergence of a resistant phenotype. These observations suggest that the inhibition of Src activity may present a novel therapeutic intervention strategy, particularly when used as an adjuvant in endocrine-resistant breast disease, with the potential to delay or prevent the acquisition of subsequent resistance to anti-growth factor therapies.

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Koochekpour, Shahriar, Michael Jeffers, Paul H. Wang, Changning Gong, Gregory A. Taylor, Lisa M. Roessler, Robert Stearman, et al. "The von Hippel-Lindau Tumor Suppressor Gene Inhibits Hepatocyte Growth Factor/Scatter Factor-Induced Invasion and Branching Morphogenesis in Renal Carcinoma Cells." Molecular and Cellular Biology 19, no. 9 (September 1, 1999): 5902–12. http://dx.doi.org/10.1128/mcb.19.9.5902.

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ABSTRACT Loss of function in the von Hippel-Lindau (VHL) tumor suppressor gene occurs in familial and most sporadic renal cell carcinomas (RCCs). VHL has been linked to the regulation of cell cycle cessation (G0) and to control of expression of various mRNAs such as for vascular endothelial growth factor. RCC cells express the Met receptor tyrosine kinase, and Met mediates invasion and branching morphogenesis in many cell types in response to hepatocyte growth factor/scatter factor (HGF/SF). We examined the HGF/SF responsiveness of RCC cells containing endogenous mutated (mut) forms of the VHL protein (VHL-negative RCC) with that of isogenic cells expressing exogenous wild-type (wt) VHL (VHL-positive RCC). We found that VHL-negative 786-0 and UOK-101 RCC cells were highly invasive through growth factor-reduced (GFR) Matrigel-coated filters and exhibited an extensive branching morphogenesis phenotype in response to HGF/SF in the three-dimensional (3D) GFR Matrigel cultures. In contrast, the phenotypes of A498 VHL-negative RCC cells were weaker, and isogenic RCC cells ectopically expressing wt VHL did not respond at all. We found that all VHL-negative RCC cells expressed reduced levels of tissue inhibitor of metalloproteinase 2 (TIMP-2) relative to the wt VHL-positive cells, implicating VHL in the regulation of this molecule. However, consistent with the more invasive phenotype of the 786-0 and UOK-101 VHL-negative RCC cells, the levels of TIMP-1 and TIMP-2 were reduced and levels of the matrix metalloproteinases 2 and 9 were elevated compared to the noninvasive VHL-positive RCC cells. Moreover, recombinant TIMPs completely blocked HGF/SF-mediated branching morphogenesis, while neutralizing antibodies to the TIMPs stimulated HGF/SF-mediated invasion in vitro. Thus, the loss of the VHL tumor suppressor gene is central to changes that control tissue invasiveness, and a more invasive phenotype requires additional genetic changes seen in some but not all RCC lines. These studies also demonstrate a synergy between the loss of VHL function and Met signaling.

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Giese, A., R. Bjerkvig, M. E. Berens, and M. Westphal. "Cost of Migration: Invasion of Malignant Gliomas and Implications for Treatment." Journal of Clinical Oncology 21, no. 8 (April 15, 2003): 1624–36. http://dx.doi.org/10.1200/jco.2003.05.063.

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Tumors of glial origin consist of a core mass and a penumbra of invasive, single cells, decreasing in numbers towards the periphery and still detectable several centimeters away from the core lesion. Several decades ago, the diffuse nature of malignant gliomas was recognized by neurosurgeons when super-radical resections using hemispherectomies failed to eradicate these tumors. Local invasiveness eventually leads to regrowth of a recurrent tumor predominantly adjacent to the resection cavity, which is not significantly altered by radiation or chemotherapy. This raises the question of whether invasive glioma cells activate cellular programs that render these cells resistant to conventional treatments. Clinical and experimental data demonstrate that glioma invasion is determined by several independent mechanisms that facilitate the spread of these tumors along different anatomic and molecular structures. A common denominator of this cellular behavior may be cell motility. Gene-expression profiling showed upregulation of genes related to motility, and functional studies demonstrated that cell motility contributes to the invasive phenotype of malignant gliomas. There is accumulating evidence that invasive glioma cells show a decreased proliferation rate and a relative resistance to apoptosis, which may contribute to chemotherapy and radiation resistance. Interestingly, interference with cell motility by different strategies results in increased susceptibility to apoptosis, indicating that this dynamic relationship can potentially be exploited as an anti-invasive treatment paradigm. In this review, we discuss mechanisms of glioma invasion, characteristics of the invasive cell, and consequences of this cellular phenotype for surgical resection, oncologic treatments, and future perspectives for anti-invasive strategies.

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Matsueda, Katsunori, Hiromitsu Kanzaki, Ryuta Takenaka, Masahiro Nakagawa, Kazuhiro Matsueda, Masaya Iwamuro, Seiji Kawano, et al. "Clinical and phenotypical characteristics of submucosal invasive carcinoma in non-ampullary duodenal cancer." PLOS ONE 16, no. 8 (August 27, 2021): e0256797. http://dx.doi.org/10.1371/journal.pone.0256797.

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Objective The rare incidence of submucosal invasive non-ampullary duodenal carcinoma has led to scant information in literature; therefore, we compared the clinicopathological features between submucosal invasive carcinoma (SM-Ca), mucosal carcinoma (M-Ca), and advanced carcinoma (Ad-Ca). Materials We retrospectively analyzed 165 patients with sporadic non-ampullary duodenal carcinomas (SNADCs) from four institutions between January 2003 and December 2018. The SNADCs were divided to three groups according to histological diagnosis: SM-Ca, M-Ca, and Ad-Ca. The clinicopathological characteristics and mucin phenotypes were compared between groups. Results Among the 165 SNADCs, 11 (7%) were classified as SM-Ca, 70 (42%) as M-Ca, and 84 (51%) as Ad-Ca. We found that all SM-Ca (P = 0.013) and most Ad-Ca (P = 0.020) lesions were located on the oral-Vater; however, an almost equal distribution of M-Ca lesions was found between the oral- and anal-Vater. No significant difference was observed between the tumor diameter of M-Ca and SM-Ca; however, 45% (5/11) of SM-Ca were ≤10 mm. A total of 73% (8/11) of SM-Ca were classified as gastric phenotype and no lesions were classified as intestinal phenotype; whereas most M-Ca were classified as intestinal phenotype (67%, 8/12). Conclusions SM-Ca lesions were all located on the oral-Vater and were highly associated with the gastric mucin phenotype, which were different from the features of most M-Ca.

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Nieman, Marvin T., Ryan S. Prudoff, Keith R. Johnson, and Margaret J. Wheelock. "N-Cadherin Promotes Motility in Human Breast Cancer Cells Regardless of Their E-Cadherin Expression." Journal of Cell Biology 147, no. 3 (November 1, 1999): 631–44. http://dx.doi.org/10.1083/jcb.147.3.631.

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E-cadherin is a transmembrane glycoprotein that mediates calcium-dependent, homotypic cell–cell adhesion and plays a role in maintaining the normal phenotype of epithelial cells. Decreased expression of E-cadherin has been correlated with increased invasiveness of breast cancer. In other systems, inappropriate expression of a nonepithelial cadherin, such as N-cadherin, by an epithelial cell has been shown to downregulate E-cadherin expression and to contribute to a scattered phenotype. In this study, we explored the possibility that expression of nonepithelial cadherins may be correlated with increased motility and invasion in breast cancer cells. We show that N-cadherin promotes motility and invasion; that decreased expression of E-cadherin does not necessarily correlate with motility or invasion; that N-cadherin expression correlates both with invasion and motility, and likely plays a direct role in promoting motility; that forced expression of E-cadherin in invasive, N-cadherin–positive cells does not reduce their motility or invasive capacity; that forced expression of N-cadherin in noninvasive, E-cadherin–positive cells produces an invasive cell, even though these cells continue to express high levels of E-cadherin; that N-cadherin–dependent motility may be mediated by FGF receptor signaling; and that cadherin-11 promotes epithelial cell motility in a manner similar to N-cadherin.

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Kang, S., B. Ryu, J. Sa, H. Kim, K. Park, S. Yu, D. Hong, and K. Kim. "P12.04.A Exosomes from glioma associated sphere forming cells induce a transition of invasive phenotype via transfer of EMP2 and CA9." Neuro-Oncology 24, Supplement_2 (September 1, 2022): ii77. http://dx.doi.org/10.1093/neuonc/noac174.269.

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Abstract Background Glioblastoma multiforme (GBM) mostly occurs local recurrence at normal parenchyme adjacent tumor despite of conventional treatment. Glioma stem like cells (GSC) forming intratumoral heterogeneity within the GBM acquired the microenvironmental adaptation by inter-exosomal contents exchange between heterogenic cells. In addition, GSC has an invasive potential as like human GBM. Therefore, we investigate whether exosomal proteins of GSC affect the normal tissue invasion in GBM. Material and Methods Exosomes were isolated by Size-Exclusion method from conditioned media and validated by Electron microscope and Immunoblot assay. Exosomal proteomics were examined with Liquid Chromatography-Mass Spectrometry (LC/MS). To produce the fluorescent exosome, bi-cistron vectors were cloned with shRNA and CD63-GFP. To identify the effect of tranfected exosome, the isolated exosomes were treated to recipient cells and examined the invasion by 3D invasion assay and mouse intracranial model. Results Firstly, we dichotomized two groups following tumor invasion at matrigel assay and GSC derived orthotopic mouse model. CSC2 and X01 GSCs revealed highly invasive phenotype whereas 83NS and 528NS GSCs did not. Exosome was isolated in each group and identified by CD63 expression or electron microscopy. In proteomics analysis, hypoxia, extracellular matrix organization, GTPase cycle related proteins were enriched in highly invasive cell’s exosome. Among them, we focused the carbonic anhydrase IX (CA9) and the epithelial membrane protein 2 (EMP2) on its permissive role to glioblastoma invasion respectively. CA9 and EMP2 mRNA and protein levels were verified in GSCs and their exosomes and the high expression levels were detected in CSC2 and X01 compared to the low one in 83NS and 528NS GSCs. To evaluate the effects of CA9 and EMP2 on exosome mediated invasion potential, viral bi-cistron vectors was composed with the target gene knockdown and the CD63 fluorescence was used to detect intracellular exosome transfer. Interestingly, the decreased expression of phosphorylated FAK, a key invasive marker, was observed after Lentiviral mediated CA9- and EMP2-knockdown in highly invasive CSC2. To identify whether CA9 and EMP2 proteins are the intracellular effector protein responsible for exosome mediated glioma invasion, the donor exosomes (Exo-CSC2-sh-CA9 and Exo-CSC2-EMP2, after Lentiviral transfection to CSC2s) were isolated and treated to the non invasive 528NS cells as recipient cells. In 3D invasion assay, Exo-CSC2-shCA9 or Exo-CSC2-shEMP2 mediated tumor invasion was significantly decreased at 528NS GSCs compared to Exo-CSC2-shEV. These features were found at mouse intracranial model as well. Conclusion Together with these, we conclude that exosome derived from GSCs induces a transition of invasive phenotype via transfer of EMP2 and CA9 proteins.

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Bryan, Richard T. "Cell adhesion and urothelial bladder cancer: the role of cadherin switching and related phenomena." Philosophical Transactions of the Royal Society B: Biological Sciences 370, no. 1661 (February 5, 2015): 20140042. http://dx.doi.org/10.1098/rstb.2014.0042.

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Cadherins are mediators of cell–cell adhesion in epithelial tissues. E-cadherin is a known tumour suppressor and plays a central role in suppressing the invasive phenotype of cancer cells. However, the abnormal expression of N- and P-cadherin (‘cadherin switching’, CS) has been shown to promote a more invasive and m̀alignant phenotype of cancer, with P-cadherin possibly acting as a key mediator of invasion and metastasis in bladder cancer. Cadherins are also implicated in numerous signalling events related to embryonic development, tissue morphogenesis and homeostasis. It is these wide ranging effects and the serious implications of CS that make the cadherin cell adhesion molecules and their related pathways strong candidate targets for the inhibition of cancer progression, including bladder cancer. This review focuses on CS in the context of bladder cancer and in particular the switch to P-cadherin expression, and discusses other related molecules and phenomena, including EpCAM and the development of the cancer stem cell phenotype.

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Boudreau, Nancy, Catherine Andrews, Anabella Srebrow, Ali Ravanpay, and David A. Cheresh. "Induction of the Angiogenic Phenotype by Hox D3." Journal of Cell Biology 139, no. 1 (October 6, 1997): 257–64. http://dx.doi.org/10.1083/jcb.139.1.257.

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Angiogenesis is characterized by distinct phenotypic changes in vascular endothelial cells (EC). Evidence is provided that the Hox D3 homeobox gene mediates conversion of endothelium from the resting to the angiogenic/invasive state. Stimulation of EC with basic fibroblast growth factor (bFGF) resulted in increased expression of Hox D3, integrin αvβ3, and the urokinase plasminogen activator (uPA). Hox D3 antisense blocked the ability of bFGF to induce uPA and integrin αvβ3 expression, yet had no effect on EC cell proliferation or bFGF-mediated cyclin D1 expression. Expression of Hox D3, in the absence of bFGF, resulted in enhanced expression of integrin αvβ3 and uPA. In fact, sustained expression of Hox D3 in vivo on the chick chorioallantoic membrane retained EC in this invasive state and prevented vessel maturation leading to vascular malformations and endotheliomas. Therefore, Hox D3 regulates EC gene expression associated with the invasive stage of angiogenesis.

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Li, Yuejuan, Dianhua Jiang, Jiurong Liang, Eric B. Meltzer, Alice Gray, Riu Miura, Lise Wogensen, Yu Yamaguchi, and Paul W. Noble. "Severe lung fibrosis requires an invasive fibroblast phenotype regulated by hyaluronan and CD44." Journal of Experimental Medicine 208, no. 7 (June 27, 2011): 1459–71. http://dx.doi.org/10.1084/jem.20102510.

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Tissue fibrosis is a major cause of morbidity, and idiopathic pulmonary fibrosis (IPF) is a terminal illness characterized by unremitting matrix deposition in the lung. The mechanisms that control progressive fibrosis are unknown. Myofibroblasts accumulate at sites of tissue remodeling and produce extracellular matrix components such as collagen and hyaluronan (HA) that ultimately compromise organ function. We found that targeted overexpression of HAS2 (HA synthase 2) by myofibroblasts produced an aggressive phenotype leading to severe lung fibrosis and death after bleomycin-induced injury. Fibroblasts isolated from transgenic mice overexpressing HAS2 showed a greater capacity to invade matrix. Conditional deletion of HAS2 in mesenchymal cells abrogated the invasive fibroblast phenotype, impeded myofibroblast accumulation, and inhibited the development of lung fibrosis. Both the invasive phenotype and the progressive fibrosis were inhibited in the absence of CD44. Treatment with a blocking antibody to CD44 reduced lung fibrosis in mice in vivo. Finally, fibroblasts isolated from patients with IPF exhibited an invasive phenotype that was also dependent on HAS2 and CD44. Understanding the mechanisms leading to an invasive fibroblast phenotype could lead to novel approaches to the treatment of disorders characterized by severe tissue fibrosis.

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Clarke, Joanna. "Metabolic defect causes invasive phenotype in RA T cells." Nature Reviews Rheumatology 17, no. 3 (January 8, 2021): 129. http://dx.doi.org/10.1038/s41584-021-00572-8.

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Kang, Kyu Sub, Yoon Pyo Choi, Ming-Qing Gao, Suki Kang, Baek Gil Kim, Joo Hyun Lee, Mi Jeong Kwon, Young Kee Shin, and Nam Hoon Cho. "CD24+ ovary cancer cells exhibit an invasive mesenchymal phenotype." Biochemical and Biophysical Research Communications 432, no. 2 (March 2013): 333–38. http://dx.doi.org/10.1016/j.bbrc.2013.01.102.

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Ramsay, A. K., S. R. C. McCracken, M. Soofi, J. Fleming, A. X. Yu, I. Ahmad, R. Morland, et al. "ERK5 signalling in prostate cancer promotes an invasive phenotype." British Journal of Cancer 104, no. 4 (January 25, 2011): 664–72. http://dx.doi.org/10.1038/sj.bjc.6606062.

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Bettum, Ingrid J., Saurabh S. Gorad, Anna Barkovskaya, Solveig Pettersen, Siver A. Moestue, Kotryna Vasiliauskaite, Ellen Tenstad, et al. "Metabolic reprogramming supports the invasive phenotype in malignant melanoma." Cancer Letters 366, no. 1 (September 2015): 71–83. http://dx.doi.org/10.1016/j.canlet.2015.06.006.

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Schwartz, Gary K., Henry Wang, Nina Lampen, Nasser Altorki, David Kelsen, and Anthony P. Albino. "Defining the invasive phenotype of proximal gastric cancer cells." Cancer 73, no. 1 (January 1, 1994): 22–27. http://dx.doi.org/10.1002/1097-0142(19940101)73:1<22::aid-cncr2820730106>3.0.co;2-o.

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Gordon, Linda A., Kellie T. Mulligan, Helen Maxwell-Jones, Matthew Adams, Rosemary A. Walker, and J. Louise Jones. "Breast cell invasive potential relates to the myoepithelial phenotype." International Journal of Cancer 106, no. 1 (June 3, 2003): 8–16. http://dx.doi.org/10.1002/ijc.11172.

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Baxter, M. Aaron, Thomas F. Fahlen, Rebecca L. Wilson, and Bradley D. Jones. "HilE Interacts with HilD and Negatively Regulates hilA Transcription and Expression of the Salmonella enterica Serovar Typhimurium Invasive Phenotype." Infection and Immunity 71, no. 3 (March 2003): 1295–305. http://dx.doi.org/10.1128/iai.71.3.1295-1305.2003.

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Abstract:

ABSTRACT The ability of Salmonella enterica serovar Typhimurium to traverse the intestinal mucosa of a host is an important step in its ability to initiate gastrointestinal disease. The majority of the genes required for this invasive characteristic are encoded on Salmonella pathogenicity island 1 (SPI1), and their expression is controlled by the transcriptional activator HilA, a member of the OmpR/ToxR family of proteins. A variety of genes (hilC, hilD, fis, sirA/barA, csrAB, phoB, fadD, envZ/ompR, fliZ, hilE, ams, lon, pag, and hha) have been identified that exert positive or negative effects on hilA expression, although the mechanisms by which these gene products function remain relatively unclear. Recent work indicates that the small DNA-binding protein, Hha, has a significant role in repressing hilA transcription and the invasive phenotype, particularly in response to osmolarity signals. We have characterized the Salmonella-specific gene, hilE, and found that it plays an important regulatory role in hilA transcription and invasion gene expression. Mutation of hilE causes derepression of hilA transcription, and overexpression of hilE superrepresses hilA expression and the invasive phenotype. Bacterial two-hybrid experiments indicate that the HilE protein interacts with HilD, suggesting a possible mechanism for HilE negative regulation of hilA gene expression and the Salmonella invasive phenotype. Finally, we have found that the hilE gene resides on a region of the serovar Typhimurium chromosome that has many characteristics of a pathogenicity island.

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Journal articles on the topic 'Invasive phenotype'

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