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1
Shive, Heather R., John S. House, Jordan L. Ferguson, Dereje D. Jima, Aubrie A. Selmek, and Dillon T. Lloyd. "Abstract PR011: Characterization of the precancerous and cancer microenvironment in a zebrafish sarcoma model." Clinical Cancer Research 28, no. 18_Supplement (September 15, 2022): PR011. http://dx.doi.org/10.1158/1557-3265.sarcomas22-pr011.
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Abstract Contributions of the microenvironment to soft tissue sarcoma progression are relatively undefined, representing a major impediment to identifying essential regulatory networks in sarcomagenesis. Furthermore, genetic and molecular characteristics that distinguish precancerous versus cancerous microenvironments are not well known across human cancer types. While animal models have the potential to reveal these complex processes, significant impediments to such inquiries include (1) the difficulty in distinguishing microenvironmental cells from precancerous or cancer cells in tissue specimens; and (2) the challenge in defining a discrete tissue with known cancer predilection that represents a precancerous microenvironment. We developed a unique zebrafish model that allows segregation of microenvironmental, precancerous, and cancerous cell populations by fluorescence-activated cell sorting. This model exhibits high predilection for malignant peripheral nerve sheath tumor (MPNST), a type of soft tissue sarcoma with a particularly poor prognosis due to aggressive growth, limited response to conventional treatment, and ineffective targeted therapy options. Using RNA-seq, we profiled the transcriptomes of microenvironmental cells from our zebrafish MPNST model and determined that the precancerous and cancerous microenvironments exhibit broad activation of inflammatory and immune-associated signaling networks. Markers for both M1 and M2 macrophage polarization were upregulated in precancerous and cancerous microenvironments, suggesting the presence of a mixed macrophage population during sarcomagenesis. Patterns of ligand and receptor expression based on a previously defined human ligand-receptor network identified significant upregulation of multiple tumor-promoting ligands in both precancerous and cancerous microenvironments. We also identified specific ligand-receptor pairs that may mediate key signaling events during sarcoma initiation and progression. Together this work provide new insight into distinguishing characteristics of the cancer-prone cellular microenvironment that may promote MPNST initiation and progression in vertebrates. Citation Format: Heather R. Shive, John S. House, Jordan L. Ferguson, Dereje D. Jima, Aubrie A. Selmek, Dillon T. Lloyd. Characterization of the precancerous and cancer microenvironment in a zebrafish sarcoma model [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr PR011.
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Campbell, Caroline J., and Brian W. Booth. "The Influence of the Normal Mammary Microenvironment on Breast Cancer Cells." Cancers 15, no. 3 (January 18, 2023): 576. http://dx.doi.org/10.3390/cancers15030576.
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The tumor microenvironment is recognized as performing a critical role in tumor initiation, progression, and metastasis of many cancers, including breast cancer. The breast cancer microenvironment is a complex mixture of cells consisting of tumor cells, immune cells, fibroblasts, and vascular cells, as well as noncellular components, such as extracellular matrix and soluble products. The interactions between the tumor cells and the tumor microenvironment modulate tumor behavior and affect the responses of cancer patients to therapies. The interactions between tumor cells and the surrounding environment can include direct cell-to-cell contact or through intercellular signals over short and long distances. The intricate functions of the tumor microenvironment in breast cancer have led to increased research into the tumor microenvironment as a possible therapeutic target of breast cancer. Though expanded research has shown the clear importance of the tumor microenvironment, there is little focus on how normal mammary epithelial cells can affect breast cancer cells. Previous studies have shown the normal breast microenvironment can manipulate non-mammary stem cells and tumor-derived cancer stem cells to participate in normal mammary gland development. The tumorigenic cells lose their tumor-forming capacity and are “redirected” to divide into “normal”, non-tumorigenic cells. This cellular behavior is “cancer cell redirection”. This review will summarize the current literature on cancer cell redirection and the normal mammary microenvironment’s influence on breast cancer cells.
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Gibson, Spencer, Tricia Choquette, Elizabeth S. Henson, Xioyan Yang, and James B. Johnston. "Abstract 2516: Analysis of CLL Celllular Environment and Response (ACCER) is a novel method to understand the microenvironment in CLL." Cancer Research 83, no. 7_Supplement (April 4, 2023): 2516. http://dx.doi.org/10.1158/1538-7445.am2023-2516.
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Abstract Microenvironments such as lymph nodes and bone marrow allow chronic lymphocytic leukemia (CLL) cells to survive after drug treatments. There are limited methods to study the to study the contribution of the microenvironment. We have adapted a solid tumour microenvironment cell culture system that provides elements of the CLL microenvironment called Analysis of CLL Cellular Environment and Response (ACCER). We optimized the cell number for patient’s primary CLL cells and HS-5 human bone marrow stromal cell line that will give sufficient cell number and viability with the ACCER. We then determined the amount of collagen type 1 to give the best extracellular matrix to seed CLL cells to the membrane. Finally, we determined that ACCER provide CLL cell protection against cell death following treatment with fludarabine and ibrutinib compared to co-culture conditions. This describes novel microenvironment model to investigate factors that promote drug resistance and cell survival in CLL. In the future, this will further validate new treatment strategies to overcome microenvironmental CLL cell survival signals. Citation Format: Spencer Gibson, Tricia Choquette, Elizabeth S. Henson, Xioyan Yang, James B. Johnston. Analysis of CLL Celllular Environment and Response (ACCER) is a novel method to understand the microenvironment in CLL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2516.
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Aber, Etan R., Cristina F. Contreras, Mohd Omar Sikder, Kathy P. Li, Greta E. Forbes, Vishaka Gopalan, Sridhar Hannenhalli, and Rosandra N. Kaplan. "Abstract LB308: Transcriptional profiling uncovers a unified program underlying the human metastatic and adjacent microenvironments." Cancer Research 84, no. 7_Supplement (April 5, 2024): LB308. http://dx.doi.org/10.1158/1538-7445.am2024-lb308.
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Abstract Metastasis is the primary cause of death in patients with solid tumors, yet the treatment-refractory metastatic microenvironment is poorly characterized. To gain a comprehensive understanding of microenvironmental regulation of human metastasis, we performed single-cell RNA sequencing covering endothelial, stromal, myeloid, lymphoid, and malignant cells from 28 lung and liver samples of the metastatic microenvironment and metastasis-free adjacent microenvironment from patients with metastatic adrenocortical carcinoma compared to healthy donors for a total of 275,903 cells. We discovered that the adjacent microenvironment in patients with metastatic cancer is significantly different from healthy tissue without cancer: The adjacent microenvironment has many immunosuppressive and pro-tumorigenic features similar to primary tumor and metastatic tissue. As adjacent tissues are potential sites for subsequent metastasis, the shared changes between the adjacent and metastatic microenvironments suggest that these elements of the treatment-refractory metastatic microenvironment may dictate metastasis. Importantly, these pathologic features of the adjacent and metastatic microenvironments associate with poor outcomes for patients and may be targetable. Lastly, we identify a mechanism by which tumor cells may be remotely driving and coordinating these changes in both the metastatic and adjacent microenvironments. Taken together, our study identifies shared and microenvironment-specific changes underlying a global program of metastasis. Citation Format: Etan R. Aber, Cristina F. Contreras, Mohd Omar Sikder, Kathy P. Li, Greta E. Forbes, Vishaka Gopalan, Sridhar Hannenhalli, Rosandra N. Kaplan. Transcriptional profiling uncovers a unified program underlying the human metastatic and adjacent microenvironments [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB308.
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Bischoff, Philip, Alexandra Trinks, Benedikt Obermayer, Jan Patrick Pett, Jennifer Wiederspahn, Florian Uhlitz, Xizi Liang, et al. "Single-cell RNA sequencing reveals distinct tumor microenvironmental patterns in lung adenocarcinoma." Oncogene 40, no. 50 (October 18, 2021): 6748–58. http://dx.doi.org/10.1038/s41388-021-02054-3.
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AbstractRecent developments in immuno-oncology demonstrate that not only cancer cells, but also the tumor microenvironment can guide precision medicine. A comprehensive and in-depth characterization of the tumor microenvironment is challenging since its cell populations are diverse and can be important even if scarce. To identify clinically relevant microenvironmental and cancer features, we applied single-cell RNA sequencing to ten human lung adenocarcinomas and ten normal control tissues. Our analyses revealed heterogeneous carcinoma cell transcriptomes reflecting histological grade and oncogenic pathway activities, and two distinct microenvironmental patterns. The immune-activated CP²E microenvironment was composed of cancer-associated myofibroblasts, proinflammatory monocyte-derived macrophages, plasmacytoid dendritic cells and exhausted CD8+ T cells, and was prognostically unfavorable. In contrast, the inert N³MC microenvironment was characterized by normal-like myofibroblasts, non-inflammatory monocyte-derived macrophages, NK cells, myeloid dendritic cells and conventional T cells, and was associated with a favorable prognosis. Microenvironmental marker genes and signatures identified in single-cell profiles had progonostic value in bulk tumor profiles. In summary, single-cell RNA profiling of lung adenocarcinoma provides additional prognostic information based on the microenvironment, and may help to predict therapy response and to reveal possible target cell populations for future therapeutic approaches.
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AbdelFattah, HebatAllah Samy, Mayar Tarek Ibrahim, Mostafa Mahmoud Nasr, and Shaimaa Nasr Nasr Amin. "Cell Signaling in Cancer Microenvironment." International Journal of Advanced Biomedicine 2, no. 2 (May 1, 2017): 47–51. http://dx.doi.org/10.18576/ab/020204.
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Loberg, Robert D., Christopher J. Logothetis, Evan T. Keller, and Kenneth J. Pienta. "Pathogenesis and Treatment of Prostate Cancer Bone Metastases: Targeting the Lethal Phenotype." Journal of Clinical Oncology 23, no. 32 (November 10, 2005): 8232–41. http://dx.doi.org/10.1200/jco.2005.03.0841.
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Traditionally, prostate cancer treatment, as well as all cancer treatment, has been designed to target the tumor cell directly via various hormonal and chemotherapeutic agents. Recently, the realization that cancer cells exist in complex microenvironments that are essential for the tumorigenic and metastatic potential of the cancer cells is starting the redefine the paradigm for cancer therapy. The propensity of prostate cancer cells to metastasize to bone is leading to the design of novel therapies targeting both the cancer cell as well as the bone microenvironment. Tumor cells in the bone interact with the extracellular matrix, stromal cells, osteoblasts, osteoclasts, and endothelial cells to promote tumor-cell survival and proliferation leading to a lethal phenotype that includes increased morbidity and mortality for patients with advanced prostate cancer. Several strategies are being developed that target these complex tumor cell–microenvironment interactions and target the signal transduction pathways of other cells important to the development of metastases, including the osteoclasts, osteoblasts, and endothelial cells of the bone microenvironment. Current and new therapies in metastatic prostate cancer will comprise a multitargeted approach aimed at both the tumor cell and the tumor microenvironment. Here, we review the current therapeutic strategies for targeting the prostate cancer–bone microenvironment and several single- and multiagent targeted approaches to the treatment of advanced prostate cancer that are under development.
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Kim, Jaehong. "Regulation of Immune Cell Functions by Metabolic Reprogramming." Journal of Immunology Research 2018 (2018): 1–12. http://dx.doi.org/10.1155/2018/8605471.
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Recent findings show that the metabolic status of immune cells can determine immune responses. Metabolic reprogramming between aerobic glycolysis and oxidative phosphorylation, previously speculated as exclusively observable in cancer cells, exists in various types of immune and stromal cells in many different pathological conditions other than cancer. The microenvironments of cancer, obese adipose, and wound-repairing tissues share common features of inflammatory reactions. In addition, the metabolic changes in macrophages and T cells are now regarded as crucial for the functional plasticity of the immune cells and responsible for the progression and regression of many pathological processes, notably cancer. It is possible that metabolic changes in the microenvironment induced by other cellular components are responsible for the functional plasticity of immune cells. This review explores the molecular mechanisms responsible for metabolic reprogramming in macrophages and T cells and also provides a summary of recent updates with regard to the functional modulation of the immune cells by metabolic changes in the microenvironment, notably the tumor microenvironment.
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Garre, Elena, Anna Gustafsson, Maria Carmen Leiva, Joakim Håkansson, Anders Ståhlberg, Anikó Kovács, and Göran Landberg. "Breast Cancer Patient-Derived Scaffolds Can Expose Unique Individual Cancer Progressing Properties of the Cancer Microenvironment Associated with Clinical Characteristics." Cancers 14, no. 9 (April 26, 2022): 2172. http://dx.doi.org/10.3390/cancers14092172.
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Breast cancer is a heterogeneous disease in terms of cellular and structural composition, and besides acquired aggressive properties in the cancer cell population, the surrounding tumor microenvironment can affect disease progression and clinical behaviours. To specifically decode the clinical relevance of the cancer promoting effects of individual tumor microenvironments, we performed a comprehensive test of 110 breast cancer samples using a recently established in vivo-like 3D cell culture platform based on patient-derived scaffolds (PDSs). Cell-free PDSs were recellularized with three breast cancer cell lines and adaptation to the different patient-based microenvironments was monitored by quantitative PCR. Substantial variability in gene expression between individual PDS cultures from different patients was observed, as well as between different cell lines. Interestingly, specific gene expression changes in the PDS cultures were significantly linked to prognostic features and clinical information from the original cancer. This link was even more pronounced when ERα-status of cell lines and PDSs matched. The results support that PDSs cultures, including a cancer cell line of relevant origin, can monitor the activity of the tumor microenvironment and reveal unique information about the malignancy-inducing properties of the individual cancer niche and serve as a future complementary diagnostic tool for breast cancer.
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Leach, Damien, Alison Buxton, Gilberto Serrano de Almeida, Grant Buchanan, and Charlotte Lynne Bevan. "Androgen Activity in the Primary and Metastatic Prostate Cancer Microenvironments Influences Disease Progression and Patient Outcomes." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A1011. http://dx.doi.org/10.1210/jendso/bvab048.2068.
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Abstract Background: Cancers do not exist in isolation, surrounding tumours are supportive cells, which create the microenvironment in which cancer cells reside. In the prostate cancer (PCa), androgen receptor (AR) signalling in the surrounding fibroblasts is strikingly distinct from that within PCa cells, and has specific functions to produce, maintain, and modulate the extracellular matrix (ECM) which surrounds and interacts with PCa cells. The supportive cells of metastatic sites differ from those in the primary site and produce different types of cellular microenvironments. Since the advent of second generation anti-androgen therapy there has been an increase in the presence of liver metastasis. This project investigates how AR and anti-androgen therapy affect the prostate liver microenvironment and the subsequent effects on cancer. Results: Analysis of microenvironment of primary and metastatic sites indicates transcriptional responses distinct from that seen in PCa cells. This is exemplified by proliferation responses to androgen and anti-androgens in microenvironment cells being the reverse to that seen in Pca cells. Dichotomising microdissected PCa patient material of matched cancer and stromal tissue, based on stromal AR level shows distinct transcriptional profiles in the matched cancer cells. From previous studies, we know AR status in cancer adjacent fibroblasts (CAFs) of the primary tumor inversely associates with patient outcomes. Analysis of single cell CAFs and microdissected stromal samples points to a potential sub population of CAFs with this AR status. Conditioned media from liver and prostate fibroblast cells suggests that inactivation of AR signalling produces proliferative paracrine signals that can affect cancer cell growth. AR in primary site fibroblast and liver stellate cells regulates secretome and ECM production in the primary and metastatic site. Prostates and livers from enzalutamide treated mice showed changes in collagen fibres compared to control mice, as visualised by picro-direct-red staining. We cultured PCa cells within 3D-ECM microenvironments created in vitro from prostate fibroblasts or liver cells. The different 3D-ECM were able to produce changes in PCa cells, including gene transcription, intracellular signalling pathways, and proliferation and apoptotic responses. These data suggest that the responses of primary and metastatic microenvironments to androgens and anti-androgens can influence phosphorylation of intracellular pathways leading to alterations in gene transcription. Furthermore, the transcriptional responses of cancer cells in vitro to changes in microenvironmental AR signalling can be used to predict patient outcomes. Conclusions: Our data suggests that anti-AR therapy produces organ microenvironment-specific signals that influence the response of prostate cancer to treatments and affects patient outcomes.
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Deng, Shuzhi, Shimeng Wang, Xueke Shi, and Hongmei Zhou. "Microenvironment in Oral Potentially Malignant Disorders: Multi-Dimensional Characteristics and Mechanisms of Carcinogenesis." International Journal of Molecular Sciences 23, no. 16 (August 11, 2022): 8940. http://dx.doi.org/10.3390/ijms23168940.
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Oral potentially malignant disorders (OPMDs) are a group of diseases involving the oral mucosa and that have a risk of carcinogenesis. The microenvironment is closely related to carcinogenesis and cancer progression by regulating the immune response, cell metabolic activities, and mechanical characteristics. Meanwhile, there are extensive interactions between the microenvironments that remodel and provide favorable conditions for cancer initiation. However, the changes, exact roles, and interactions of microenvironments during the carcinogenesis of OPMDs have not been fully elucidated. Here, we present an updated landscape of the microenvironments in OPMDs, emphasizing the changes in the immune microenvironment, metabolic microenvironment, mechanical microenvironment, and neural microenvironment during carcinogenesis and their carcinogenic mechanisms. We then propose an immuno–metabolic–mechanical–neural interaction network to describe their close relationships. Lastly, we summarize the therapeutic strategies for targeting microenvironments, and provide an outlook on future research directions and clinical applications. This review depicts a vivid microenvironment landscape and sheds light on new strategies to prevent the carcinogenesis of OPMDs.
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Faurobert, Eva, Anne-Pascale Bouin, and Corinne Albiges-Rizo. "Microenvironment, tumor cell plasticity, and cancer." Current Opinion in Oncology 27, no. 1 (January 2015): 64–70. http://dx.doi.org/10.1097/cco.0000000000000154.
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Kim, Jisoo, Jinah Jang, and Dong-Woo Cho. "Recapitulating the Cancer Microenvironment Using Bioprinting Technology for Precision Medicine." Micromachines 12, no. 9 (September 17, 2021): 1122. http://dx.doi.org/10.3390/mi12091122.
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The complex and heterogenous nature of cancer contributes to the development of cancer cell drug resistance. The construction of the cancer microenvironment, including the cell–cell interactions and extracellular matrix (ECM), plays a significant role in the development of drug resistance. Traditional animal models used in drug discovery studies have been associated with feasibility issues that limit the recapitulation of human functions; thus, in vitro models have been developed to reconstruct the human cancer system. However, conventional two-dimensional and three-dimensional (3D) in vitro cancer models are limited in their ability to emulate complex cancer microenvironments. Advances in technologies, including bioprinting and cancer microenvironment reconstruction, have demonstrated the potential to overcome some of the limitations of conventional models. This study reviews some representative bioprinted in vitro models used in cancer research, particularly fabrication strategies for modeling and consideration of essential factors needed for the reconstruction of the cancer microenvironment. In addition, we highlight recent studies that applied such models, including application in precision medicine using advanced bioprinting technologies to fabricate biomimetic cancer models. Furthermore, we discuss current challenges in 3D bioprinting and suggest possible strategies to construct in vitro models that better mimic the pathophysiology of the cancer microenvironment for application in clinical settings.
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Cacciatore, Matilde, Carla Guarnotta, Marco Calvaruso, Sabina Sangaletti, Ada Maria Florena, Vito Franco, Mario Paolo Colombo, and Claudio Tripodo. "Microenvironment-Centred Dynamics in Aggressive B-Cell Lymphomas." Advances in Hematology 2012 (2012): 1–12. http://dx.doi.org/10.1155/2012/138079.
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Aggressive B-cell lymphomas share high proliferative and invasive attitudes and dismal prognosis despite heterogeneous biological features. In the interchained sequence of events leading to cancer progression, neoplastic clone-intrinsic molecular events play a major role. Nevertheless, microenvironment-related cues have progressively come into focus as true determinants for this process. The cancer-associated microenvironment is a complex network of nonneoplastic immune and stromal cells embedded in extracellular components, giving rise to a multifarious crosstalk with neoplastic cells towards the induction of a supportive milieu. The immunological and stromal microenvironments have been classically regarded as essential partners of indolent lymphomas, while considered mainly negligible in the setting of aggressive B-cell lymphomas that, by their nature, are less reliant on external stimuli. By this paper we try to delineate the cardinal microenvironment-centred dynamics exerting an influence over lymphoid clone progression in aggressive B-cell lymphomas.
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Blaylock, Russell L. "Viruses and tumor cell microenvironment: A brief summary." Surgical Neurology International 10 (August 9, 2019): 160. http://dx.doi.org/10.25259/sni_351_2019.
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An infectious etiology for a number of cancers has been entertained for over 100 years and modern studies have confirmed that a number of viruses are linked to cancer induction. While a large number of viruses have been demonstrated in a number of types of cancers, most such findings have been dismissed in the past as opportunistic infections, especially with persistent viruses with high rates of infectivity of the world’s populations. More recent studies have clearly shown that while not definitely causing these cancers, these viruses appear capable of affecting the biology of these tumors in such a way as to make them more aggressive and more resistant to conventional treatments. The term oncomodulatory viruses have been used to describe this phenomenon. A number of recent studies have shown a growing number of ways; these oncomodulatory viruses can alter the pathology of these tumors by affecting cell signaling, cell metabolism, apoptosis mechanisms, cell-cell communication, inflammation, antitumor immunity suppression, and angiogenesis. We are also learning that much of the behavior of tumors depends on cancer stem cells and stromal cells within the tumor microenvironment, which participate in extensive, dynamic crosstalk known to affect tumor behavior. Cancer stem cells have been found to be particularly susceptible to infection by human cytomegaloviruses. In a number of studies, it has been shown that while only a select number of cells are actually infected with the virus, numerous viral proteins are released into the cancer and stromal cells in the microenvironment and these viral proteins are known to affect tumor behavior and aggressiveness.
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Cervantes-Valencia, Jesus Lizbeth, and Robert M. Kao. "From Cancer Microenvironment to Myofibroblasts." American Biology Teacher 85, no. 1 (January 1, 2023): 12–16. http://dx.doi.org/10.1525/abt.2023.85.1.12.
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One of the important mechanisms in cancer cell metastasis is the cellular function of a specific cell type called myofibroblast cells. Myofibroblast cells are unique cell types that play an important role in the cancer cell microenvironment. As a step toward integrating the latest peer-reviewed cancer research findings into a general biology remote learning setting, we developed an innovative guest speaker talk to engage first-year undergraduates to develop a prediction on tumor microenvironment. In our article, we describe integrated remote approaches using Jamboard and reflective mentoring to validate and reflect on undergraduate team responses within an inclusive and equitable framework. These teaching and mentoring strategies provide a framework for senior undergraduates to be transformative role model scholars that inspire the next generation of Latinx and Native American undergraduates in important topics related to health and environment and the process of science for general biology undergraduates.
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Shin, Eunah, and Ja Seung Koo. "Cell Component and Function of Tumor Microenvironment in Thyroid Cancer." International Journal of Molecular Sciences 23, no. 20 (October 20, 2022): 12578. http://dx.doi.org/10.3390/ijms232012578.
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Thyroid cancer is the most common cancer in the endocrine system. Most thyroid cancers have good prognosis, but some of them are resistant to treatment or show aggressive behavior. Like other tumors, thyroid cancers harbor tumor microenvironment (TME) composed of cancer associated fibroblasts (CAF) and immune cells. Autoimmune lymphocytic thyroiditis can occur in the thyroid, and it may be associated with cancer development. TME is involved in tumor progression through various mechanisms: (1) CAF is involved in tumor progression through cell proliferation and extracellular matrix (ECM) remodeling; and (2) immune cells are involved in tumor progression through cell proliferation, angiogenesis, epithelial mesenchymal transformation (EMT), and immune suppression. These events are activated by various cytokines, chemokines, and metabolites secreted from cells that comprise TME. This review is focused on how CAF and immune cells, two important cell components of thyroid cancer TME, are involved in tumor progression, and will explore their potential as therapeutic targets.
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Huntsman, David. "Abstract IA008: Rare ovarian cancers: the sequelae of specific interactions between cell contexts mutations and microenvironments." Cancer Research 84, no. 5_Supplement_2 (March 4, 2024): IA008. http://dx.doi.org/10.1158/1538-7445.ovarian23-ia008.
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Abstract There are many pathologically and clinically distinct types of ovarian cancer and uterine cancers. These are not flavors of the same disease nor can they be solely explained by different mutations or other genomic findings; rather each may be thought to represent distinct interactions between cells of origin, mutations, and the microenvironment in which these cancers occur. Although many know gaps remain this may explain many curious features of these cancers. Fors instance, how endometrioid and clear cell carcinomas have similar mutations yet are distinct biologic and clinical entities. Also, why they occur at similar rates from ovarian endometriomas, yet clear cell cancers are much rarer in the endometrium. As an example of the importance microenvironment, findings will be presented suggesting that expression of Cystathionine gamma-lyase (CTH or CSE), a key enzyme within the transsulfuration pathway, enables CCC precursor cells to survive in endometriotic cysts becoming a defining feature of this cancer, one that may explain its biologic properties, aggressive course and relative chemoresistance. Other cancers will be considered using this model including rare stromal cancers. Citation Format: David Huntsman. Rare ovarian cancers: the sequelae of specific interactions between cell contexts mutations and microenvironments [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr IA008.
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Saab, Juan J. Apiz, Lindsey N. Dzierozynski, Patrick B. Jonker, Zhou Zhu, Riona N. Chen, Moses Oh, Colin Sheehan, Kay F. Macleod, Christopher R. Weber, and Alexander Muir. "Abstract B003: Pancreatic cancer cells activate arginine biosynthesis to adapt to myeloid-driven amino acid stress in the tumor microenvironment." Cancer Research 82, no. 22_Supplement (November 15, 2022): B003. http://dx.doi.org/10.1158/1538-7445.panca22-b003.
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Abstract Nutrient stress in the tumor microenvironment requires cancer cells to adopt adaptive metabolic programs to maintain survival and proliferation. Therefore, knowledge of microenvironmental nutrient levels and how cancer cells cope with such nutrition is critical to understand the metabolism underpinning cancer cell biology. Previously, we performed quantitative metabolomics of the interstitial fluid (the local perfusate) of pancreatic ductal adenocarcinoma (PDAC) tumors to comprehensively characterize nutrient availability in the microenvironment of these tumors. We have used this information to develop Tumor Interstitial Fluid Medium (TIFM), a cell culture medium that contains nutrient levels representative of the PDAC microenvironment, enabling study of PDAC metabolism under physiological nutrition. By transcriptomic analysis, we show that PDAC cells cultured in TIFM, compared to standard culture models, adopt a cellular state more similar to PDAC cells in tumors. Using the TIFM model, we then identified arginine biosynthesis as a critical metabolic adaptation PDAC cells engage to cope with microenvironmental nutrition. We further find that arginine biosynthesis enables PDAC cells to cope with microenvironmental arginine starvation, which we show is driven by myeloid cells in PDAC tumors. Altogether, these data show that nutrient availability in the microenvironment is an important determinant of PDAC metabolism and behavior, and models incorporating tumor nutrition enable detailed and mechanistic study of microenvironmentally-programmed PDAC cell states and phenotypes. Further, through use of the TIFM model, we identified both myeloid-driven arginine starvation as a major metabolic stress prevalent in the PDAC microenvironment, and the metabolic adaptations PDAC cells use to counter this nutritional challenge. Citation Format: Juan J. Apiz Saab, Lindsey N. Dzierozynski, Patrick B. Jonker, Zhou Zhu, Riona N. Chen, Moses Oh, Colin Sheehan, Kay F. Macleod, Christopher R. Weber, Alexander Muir. Pancreatic cancer cells activate arginine biosynthesis to adapt to myeloid-driven amino acid stress in the tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B003.
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Thienger, Phillip, and Mark A. Rubin. "Prostate cancer hijacks the microenvironment." Nature Cell Biology 23, no. 1 (January 2021): 3–5. http://dx.doi.org/10.1038/s41556-020-00616-3.
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Thienger, Phillip, and Mark A. Rubin. "Prostate cancer hijacks the microenvironment." Nature Cell Biology 23, no. 1 (January 2021): 3–5. http://dx.doi.org/10.1038/s41556-020-00616-3.
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Timmins, Matthew A., and Ingo Ringshausen. "Transforming Growth Factor-Beta Orchestrates Tumour and Bystander Cells in B-Cell Non-Hodgkin Lymphoma." Cancers 14, no. 7 (March 31, 2022): 1772. http://dx.doi.org/10.3390/cancers14071772.
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Transforming growth factor-beta (TGFB) is a critical regulator of normal haematopoiesis. Dysregulation of the TGFB pathway is associated with numerous haematological malignancies including myelofibrosis, acute myeloid leukaemia, and lymphoid disorders. TGFB has classically been seen as a negative regulator of proliferation in haematopoiesis whilst stimulating differentiation and apoptosis, as required to maintain homeostasis. Tumours frequently develop intrinsic resistant mechanisms to homeostatic TGFB signalling to antagonise its tumour-suppressive functions. Furthermore, elevated levels of TGFB enhance pathogenesis through modulation of the immune system and tumour microenvironment. Here, we review recent advances in the understanding of TGFB signalling in B-cell malignancies with a focus on the tumour microenvironment. Malignant B-cells harbour subtype-specific alterations in TGFB signalling elements including downregulation of surface receptors, modulation of SMAD signalling proteins, as well as genetic and epigenetic aberrations. Microenvironmental TGFB generates a protumoural niche reprogramming stromal, natural killer (NK), and T-cells. Increasingly, evidence points to complex bi-directional cross-talk between cells of the microenvironment and malignant B-cells. A greater understanding of intercellular communication and the context-specific nature of TGFB signalling may provide further insight into disease pathogenesis and future therapeutic strategies.
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Matarrese, Paola, Rosa Vona, Barbara Ascione, Camilla Cittadini, Annalisa Tocci, and Anna Maria Mileo. "Tumor Microenvironmental Cytokines Drive NSCLC Cell Aggressiveness and Drug-Resistance via YAP-Mediated Autophagy." Cells 12, no. 7 (March 30, 2023): 1048. http://dx.doi.org/10.3390/cells12071048.
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Dynamic reciprocity between cellular components of the tumor microenvironment and tumor cells occurs primarily through the interaction of soluble signals, i.e., cytokines produced by stromal cells to support cancer initiation and progression by regulating cell survival, differentiation and immune cell functionality, as well as cell migration and death. In the present study, we focused on the analysis of the functional response of non-small cell lung cancer cell lines elicited by the treatment with some crucial stromal factors which, at least in part, mimic the stimulus exerted in vivo on tumor cells by microenvironmental components. Our molecular and functional results highlight the role played by the autophagic machinery in the cellular response in terms of the invasive capacity, stemness and drug resistance of two non-small lung cancer cell lines treated with stromal cytokines, also highlighting the emerging role of the YAP pathway in the mutual and dynamic crosstalk between tumor cells and tumor microenvironment elements. The results of this study provide new insights into the YAP-mediated autophagic mechanism elicited by microenvironmental cytokines on non-small cell lung cancer cell lines and may suggest new potential strategies for future cancer therapeutic interventions.
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Pasquier, Jennifer, and Arash Rafii. "Role of the Microenvironment in Ovarian Cancer Stem Cell Maintenance." BioMed Research International 2013 (2013): 1–10. http://dx.doi.org/10.1155/2013/630782.
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Despite recent progresses in cancer therapy and increased knowledge in cancer biology, ovarian cancer remains a challenging condition. Among the latest concepts developed in cancer biology, cancer stem cells and the role of microenvironment in tumor progression seem to be related. Indeed, cancer stem cells have been described in several solid tumors including ovarian cancers. These particular cells have the ability to self-renew and reconstitute a heterogeneous tumor. They are characterized by specific surface markers and display resistance to therapeutic regimens. During development, specific molecular cues from the tumor microenvironment can play a role in maintaining and expanding stemness of cancer cells. The tumor stroma contains several compartments: cellular component, cytokine network, and extracellular matrix. These different compartments interact to form a permissive niche for the cancer stem cells. Understanding the molecular cues underlying this crosstalk will allow the design of new therapeutic regimens targeting the niche. In this paper, we will discuss the mechanisms implicated in the interaction between ovarian cancer stem cells and their microenvironment.
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Xu, Jiasheng, Kaili Liao, and Weimin Zhou. "Exosomes Regulate the Transformation of Cancer Cells in Cancer Stem Cell Homeostasis." Stem Cells International 2018 (September 23, 2018): 1–16. http://dx.doi.org/10.1155/2018/4837370.
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In different biological model systems, exosomes are considered mediators of cell-cell communication between different cell populations. Exosomes, as extracellular vesicles, participate in physiological and pathological processes by transmitting signaling molecules such as proteins, nucleic acids, and lipids. The tumor’s microenvironment consists of many types of cells, including cancer stem cells and mesenchymal cells. It is well known that these cells communicate with each other and thereby regulate the progression of the tumor. Recent studies have provided evidence that exosomes mediate the interactions between different types of cells in the tumor microenvironment, providing further insight into how these cells interact through exosome signaling. Cancer stem cells are a small kind of heterogeneous cells that existed in tumor tissues or cancer cell lines. These cells possess a stemness phenotype with a self-renewal ability and multipotential differentiation which was considered the reason for the failure of conventional cancer therapies and tumor recurrence. However, a highly dynamic equilibrium was found between cancer stem cells and cancer cells, and this indicates that cancer stem cells are no more special target and blocking the transformation of cancer stem cells and cancer cells seem to be a more significant therapy strategy. Whether exosomes, as an information transforming carrier between cells, regulated cancer cell transformation in cancer stem cell dynamic equilibrium and targeting exosome signaling attenuated the formation of cancer stem cells and finally cure cancers is worthy of further study.
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Figy, Christopher, Anna Guo, Veani Roshale Fernando, Saori Furuta, Fahd Al-Mulla, and Kam C. Yeung. "Changes in Expression of Tumor Suppressor Gene RKIP Impact How Cancers Interact with Their Complex Environment." Cancers 15, no. 3 (February 2, 2023): 958. http://dx.doi.org/10.3390/cancers15030958.
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Tumor microenvironment (TME) is the immediate environment where cancer cells reside in a tumor. It is composed of multiple cell types and extracellular matrix. Microenvironments can be restrictive or conducive to the progression of cancer cells. Initially, microenvironments are suppressive in nature. Stepwise accumulation of mutations in oncogenes and tumor suppressor genes enables cancer cells to acquire the ability to reshape the microenvironment to advance their growth and metastasis. Among the many genetic events, the loss-of-function mutations in tumor suppressor genes play a pivotal role. In this review, we will discuss the changes in TME and the ramifications on metastasis upon altered expression of tumor metastasis suppressor gene RKIP in breast cancer cells.
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Casson, Jake, Owen G. Davies, Carol-Anne Smith, Matthew J. Dalby, and Catherine C. Berry. "Mesenchymal stem cell-derived extracellular vesicles may promote breast cancer cell dormancy." Journal of Tissue Engineering 9 (January 2018): 204173141881009. http://dx.doi.org/10.1177/2041731418810093.
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Disseminated breast cancer cells have the capacity to metastasise to the bone marrow and reside in a dormant state within the mesenchymal stem cell niche. Research has focussed on paracrine signalling factors, such as soluble proteins, within the microenvironment. However, it is now clear extracellular vesicles secreted by resident mesenchymal stem cells into this microenvironment also play a key role in the initiation of dormancy. Dormancy encourages reduced cell proliferation and migration, while upregulating cell adhesion, thus retaining the cancer cells within the bone marrow microenvironment. Here, MCF7 breast cancer cells were treated with mesenchymal stem cell–derived extracellular vesicles, resulting in reduced migration in two-dimensional and three-dimensional culture, with reduced cell proliferation and enhanced adhesion, collectively supporting cancer cell dormancy.
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Shi, Xiaokai, Xiao Zhou, Chuang Yue, Shenglin Gao, Zhiqin Sun, Chao Lu, and Li Zuo. "A Five Collagen-Related Gene Signature to Estimate the Prognosis and Immune Microenvironment in Clear Cell Renal Cell Cancer." Vaccines 9, no. 12 (December 20, 2021): 1510. http://dx.doi.org/10.3390/vaccines9121510.
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Collagen is the main component of the extracellular matrix (ECM) and might play an important role in tumor microenvironments. However, the relationship between collagen and clear cell renal cell cancer (ccRCC) is still not fully clarified. Hence, we aimed to establish a collagen-related signature to predict the prognosis and estimate the tumor immune microenvironment in ccRCC patients. Patients with a high risk score were often correlated with unfavorable overall survival (OS) and an immunosuppressive microenvironment. In addition, the collagen-related genetic signature was highly correlated with clinical pathological features and can be considered as an independent prognostic factor in ccRCC patients. Moreover, GSEA results show that patients with a high risk grade tend to be associated with epithelial–mesenchymal junctions (EMT) and immune responses. In this study, we developed a collagen-related gene signature, which might possess the potential to predict the prognosis and immune microenvironment of ccRCC patients and function as an independent prognostic factor in ccRCC.
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Rao, Rohit, Feng Zhang, Ravinder Verma, Jincheng Wang, Dazhuan Xin, and Richard Lu. "TMIC-55. CHARACTERIZATION OF TUMOR-MICROENVIRONMENT INTERACTIONS IN GLIOBLASTOMAS AT THE SINGLE-CELL LEVEL." Neuro-Oncology 21, Supplement_6 (November 2019): vi259—vi260. http://dx.doi.org/10.1093/neuonc/noz175.1089.
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Abstract Glioblastomas are malignant brain tumors that carry a poor prognosis. The tumor microenvironment has been identified as an important regulator of tumor growth and may represent a novel target for therapy. Transcriptional subtypes of glioma are a major source of heterogeneity of expression in gliomas. Gliomas are highly heterogeneous diseases and can be classified into different subtypes including proneural, classical and mesenchymal tumors. We hypothesized that different subtypes of glioma will have different microenvironmental composition and exhibit distinct responses to therapies. To understand whether gliomas induced by different oncogenic drivers affect microenvironment composition, we induced mouse gliomas using a PDGFB and dnp53 driver to model proneural glioma and HRasV12 and dnp53 to model mesenchymal glioma, respectively. We performed single cell transcriptomic profiling to characterize the tumor microenvironment in these glioma models. We found that in the PDGFB/dnp53 glioma model had a large microglia contribution with about 30% tumor-associated microglia. In contrast, the HRasV12/dnp53 glioma model had only sparse microenvironmental cells. In addition, microglia in each model displayed subtype-specific gene expression programs, with microglia in the HRasV12/dnp53 tumor model expressing increased antigen presenting genes while increased levels of osteopontin in the PDGFB/dnp53 tumor model. To determine the tumor-microenvironment interactions, we performed receptor-ligand analysis using CellPhoneDb to identify secretory ligands that support tumor cell growth in microenvironmental cells. We found that tumor-associated pericytes are an important source of growth factor ligands in both PDGFB/dnp53 and HRasV12/dnp53 glioma models. We are investigating the contribution of microglia and pericytes to tumor growth and survival through cell depletion and pharmacological inhibition and determining whether the differences in tumor microglia between the models affects sensitivity to therapies including immunotherapy. Understanding how tumor-intrinsic signaling modulates microenvironment niches and tumor-microenvironment communications aids rational design of combinations targeting the malignant brain tumors.
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Ghotra, Veerander P. S., Jordi C. Puigvert, and Erik H. J. Danen. "The cancer stem cell microenvironment and anti-cancer therapy." International Journal of Radiation Biology 85, no. 11 (November 2009): 955–62. http://dx.doi.org/10.3109/09553000903242164.
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Arneth, Borros. "Tumor Microenvironment." Medicina 56, no. 1 (December 30, 2019): 15. http://dx.doi.org/10.3390/medicina56010015.
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Background and Objectives: The tumor microenvironment has been widely implicated in tumorigenesis because it harbors tumor cells that interact with surrounding cells through the circulatory and lymphatic systems to influence the development and progression of cancer. In addition, nonmalignant cells in the tumor microenvironment play critical roles in all the stages of carcinogenesis by stimulating and facilitating uncontrolled cell proliferation. Aim: This study aims to explore the concept of the tumor microenvironment by conducting a critical review of previous studies on the topic. Materials and Methods: This review relies on evidence presented in previous studies related to the topic. The articles included in this review were obtained from different medical and health databases. Results and Discussion: The tumor microenvironment has received significant attention in the cancer literature, with a particular focus on its role in tumor development and progression. Previous studies have identified various components of the tumor microenvironment that influence malignant behavior and progression. In addition to malignant cells, adipocytes, fibroblasts, tumor vasculature, lymphocytes, dendritic cells, and cancer-associated fibroblasts are present in the tumor microenvironment. Each of these cell types has unique immunological capabilities that determine whether the tumor will survive and affect neighboring cells. Conclusion: The tumor microenvironment harbors cancer stem cells and other molecules that contribute to tumor development and progression. Consequently, targeting and manipulating the cells and factors in the tumor microenvironment during cancer treatment can help control malignancies and achieve positive health outcomes.
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Pein, Maren, and Thordur Oskarsson. "Microenvironment in metastasis: roadblocks and supportive niches." American Journal of Physiology-Cell Physiology 309, no. 10 (November 15, 2015): C627—C638. http://dx.doi.org/10.1152/ajpcell.00145.2015.
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In many cancers, malignant cells can spread from the primary tumor through blood circulation and initiate metastasis in secondary organs. Metastatic colonization may depend not only on inherent properties of cancer cells, but also on suitable microenvironments in distant sites. Increasing evidence suggests that the nature of the microenvironment may determine the fate of disseminated cancer cells, providing either hindrance or support for cancer cell propagation. This can result in strong selective pressure where the vast majority of cancer cells, invading a secondary organ, are either eliminated or maintained in a dormant state. The ability of cancer cells to fend off or circumvent anti-metastatic signals from the stroma and the capacity to manipulate the local microenvironment towards a supporting environment, a metastatic niche, may be essential for metastatic growth. The molecular interactions between cancer cells and the stroma are still enigmatic, but recent studies are beginning to reveal their nature. Here, we discuss the interactive relationship between metastatic cancer cells and host stroma, involving selection and adaptation of metastasis-initiating cells and host tissue remodeling. Understanding the dynamic and continuously evolving cross talk between metastatic cancer cells and the stroma may be crucial when developing cancer treatments.
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Kim, Yuri, Qun Lin, Peter Glazer, and Zhong Yun. "Hypoxic Tumor Microenvironment and Cancer Cell Differentiation." Current Molecular Medicine 9, no. 4 (May 1, 2009): 425–34. http://dx.doi.org/10.2174/156652409788167113.
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Kan, Casina, Geoffrey Vargas, François Pape, and Philippe Clézardin. "Cancer Cell Colonisation in the Bone Microenvironment." International Journal of Molecular Sciences 17, no. 10 (October 4, 2016): 1674. http://dx.doi.org/10.3390/ijms17101674.
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Mier, James W. "The tumor microenvironment in renal cell cancer." Current Opinion in Oncology 31, no. 3 (May 2019): 194–99. http://dx.doi.org/10.1097/cco.0000000000000512.
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Agrawal, Ayushi, Somayeh Shahreza, Yousef Javanmardi, Nicolas Szita, and Emad Moeendarbary. "The tumour microenvironment modulates cancer cell intravasation." Organs-on-a-Chip 4 (December 2022): 100024. http://dx.doi.org/10.1016/j.ooc.2022.100024.
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Dobaño-López, Cèlia, Ferran Araujo-Ayala, Neus Serrat, Juan G. Valero, and Patricia Pérez-Galán. "Follicular Lymphoma Microenvironment: An Intricate Network Ready for Therapeutic Intervention." Cancers 13, no. 4 (February 5, 2021): 641. http://dx.doi.org/10.3390/cancers13040641.
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Follicular Lymphoma (FL), the most common indolent non-Hodgkin’s B cell lymphoma, is a paradigm of the immune microenvironment’s contribution to disease onset, progression, and heterogeneity. Over the last few years, state-of-the-art technologies, including whole-exome sequencing, single-cell RNA sequencing, and mass cytometry, have precisely dissected the specific cellular phenotypes present in the FL microenvironment network and their role in the disease. In this already complex picture, the presence of recurring mutations, including KMT2D, CREBBP, EZH2, and TNFRSF14, have a prominent contributory role, with some of them finely tuning this exquisite dependence of FL on its microenvironment. This precise characterization of the enemy (FL) and its allies (microenvironment) has paved the way for the development of novel therapies aimed at dismantling this contact network, weakening tumor cell support, and reactivating the host’s immune response against the tumor. In this review, we will describe the main microenvironment actors, together with the current and future therapeutic approaches targeting them.
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Bronevetsky, Yelena, Evan Massi, Candy Garcia, Ningchun Liu, Yewei Xing, Natalie Czeryba, Scott Wise, and James Lim. "Abstract 1782: Functional potency assay predicts CAR-T effectiveness in tumor microenvironment." Cancer Research 83, no. 7_Supplement (April 4, 2023): 1782. http://dx.doi.org/10.1158/1538-7445.am2023-1782.
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Abstract Chimeric antigen receptor (CAR) T cell therapy holds great promise for the treatment of various cancers, including solid tumors. However, attempts to model the behavior and effectiveness of CAR-T cell therapies for blood cancers and solid tumors have been challenging due to the unique tumor microenvironments in which these cancer cells are found. The tumor microenvironment (TME) is often characterized by hypoxia, increased acidity, and high interstitial fluid pressures, allowing cancer cells to effectively evade immune surveillance. This immunosuppressive TME also contributes to CAR-T cell exhaustion, thereby limiting its antitumor activity and function. To address these concerns, we have developed a proprietary cell-based assay to measure CAR-T cell potency and cytotoxic function in three-dimensional (3D) in vitro cell culture system, human acute B cell lymphoblastic leukemia mouse model, and immunosuppressive tumor microenvironments. Utilizing the AVATAR system, we replicated the oxygen and interstitial fluid pressures found in the vasculature, the bone marrow and solid tumor microenvironments. Tumor cytolysis assays were conducted in these environments to measure cell exhaustion as analyzed by flow cytometry and electrical impedance. In addition, serial tumor challenge assays were performed to examine CAR-T potency and effectiveness in TME. Proof-of-concept experiments were performed using ROR1 CAR-T cells targeting the ovarian adenocarcinoma cell line, SKOV3. CD19 CAR-T were also used targeting the acute lymphoblastic leukemia cell line, NALM6. Defined ratios of effector T cells to tumor cells was assessed to model CAR-T potency in vitro and elevated CD19 CAR-T mediated cytotoxicity was confirmed with the increased ratio of effector T cells to tumor cells in both 2D and 3D culture system. CD19 CAR-T cells also exhibited in vivo dose dependent efficacy against the systemic NALM6-Luc acute lymphoblastic leukemia (ALL) mouse model, quantified by bioluminescence (BLI) image monitoring method. Multiple pressure and oxygen settings were examined to model the cross-section of the bone marrow and solid tumor microenvironments (0 PSI to 5 PSI, 1% to 10% O2). Initial results from these screening experiments show significant decline in ROR1 CAR-T mediated cytotoxicity when performed under TME conditions. However, CD19 CAR-T showed effective cell killing under TME conditions. Interestingly, acclimating and expanding ROR1 CAR-T cells to high pressure and decreased oxygen culture conditions improved potency levels and warrants further investigation. In summary, we observe CAR-T cells comprise the tumor cell killing ability in both in vitro 3D and in vivo animal models. We also describe a physiologically relevant potency assay that incorporates hyperbaric and hypoxic incubation technology to predict the behavior of cell therapies in immunosuppressive tumor microenvironments. Citation Format: Yelena Bronevetsky, Evan Massi, Candy Garcia, Ningchun Liu, Yewei Xing, Natalie Czeryba, Scott Wise, James Lim. Functional potency assay predicts CAR-T effectiveness in tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1782.
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Flynn, Catherine M., and Dan S. Kaufman. "Donor cell leukemia: insight into cancer stem cells and the stem cell niche." Blood 109, no. 7 (November 28, 2006): 2688–92. http://dx.doi.org/10.1182/blood-2006-07-021980.
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Abstract Donor cell leukemia (DCL) is a rare complication of hematopoietic cell transplantation (HCT). Its incidence has been reported between 0.12% and 5%, although the majority of cases are anecdotal. The mechanisms of leukemogenesis in DCL may be distinct from other types of leukemia. Possible causes of DCL include oncogenic alteration or premature aging of transplanted donor cells in an immunosuppressed person. Although many studies have recently better characterized leukemic stem cells, it is important to also consider that both intrinsic cell factors and external signals from the hematopoietic microenvironment govern the developmental fate of hematopoietic stem cells (HSCs). Therefore, in cases of DCL, alteration of the microenvironment after HCT may increase the likelihood that some progeny of normal HSCs become leukemic. This complex intercommunication between cells, growth factors, and cytokines in the hematopoietic microenvironment are critical to balance HSC self-renewal, proliferation, and differentiation. However, this homeostasis is likely perturbed in the development of DCL, allowing unique insight into the stimuli that regulate normal and potentially abnormal hematopoietic development. In this article, we discuss the possible pathogenesis of DCL, its association with stem cells, and its likely dependence on a less-supportive stem cell niche.
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Madden, Matthew Z., Bradley I. Reinfeld, Melissa M. Wolf, Anna Chytil, Allison S. Cohen, Alexander Muir, Rachel A. Hongo, et al. "Nutrient partitioning in the tumor microenvironment." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 56.06. http://dx.doi.org/10.4049/jimmunol.206.supp.56.06.
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Abstract The tumor microenvironment (TME) includes cancer and infiltrating immune cells. Tumors canonically consume glucose through Warburg metabolism, a process forming the basis of cancer imaging by positron emission tomography (PET). Activated immune cells also rely on glucose, and impaired immune cell metabolism in the TME contributes to tumor progression. It remains uncertain, however, if immune cell metabolism is dysregulated in the TME by cell intrinsic programs or by competition with cancer cells for limiting nutrients. Here we used PET tracers to measure access and uptake of glucose and glutamine by specific cell subsets in the TME. Surprisingly, myeloid cells had the greatest capacity to uptake glucose in vivo, followed by T cells and cancer cells across a range of cancer models. Cancer cells, in contrast, demonstrated high glutamine uptake. This distinct nutrient partitioning was cell intrinsically programmed through mTORC1 signaling and glucose and glutamine-related gene expression. Inhibiting glutamine uptake enhanced glucose uptake across tumor resident cell types, suggesting that glutamine metabolism suppresses glucose uptake without glucose being limiting in the TME. Thus, cell intrinsic programs dictate the preferential immune and cancer cell acquisition of glucose and glutamine. Cell selective partitioning of these nutrients may be exploited to develop therapies and imaging strategies to enhance or monitor the metabolism and activities of specific cell populations in the TME.
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Kim, Go Woon, Dong Hoon Lee, Yu Hyun Jeon, Jung Yoo, So Yeon Kim, Sang Wu Lee, Ha Young Cho, and So Hee Kwon. "Glutamine Synthetase as a Therapeutic Target for Cancer Treatment." International Journal of Molecular Sciences 22, no. 4 (February 8, 2021): 1701. http://dx.doi.org/10.3390/ijms22041701.
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The significance of glutamine in cancer metabolism has been extensively studied. Cancer cells consume an excessive amount of glutamine to facilitate rapid proliferation. Thus, glutamine depletion occurs in various cancer types, especially in poorly vascularized cancers. This makes glutamine synthetase (GS), the only enzyme responsible for de novo synthesizing glutamine, essential in cancer metabolism. In cancer, GS exhibits pro-tumoral features by synthesizing glutamine, supporting nucleotide synthesis. Furthermore, GS is highly expressed in the tumor microenvironment (TME) and provides glutamine to cancer cells, allowing cancer cells to maintain sufficient glutamine level for glutamine catabolism. Glutamine catabolism, the opposite reaction of glutamine synthesis by GS, is well known for supporting cancer cell proliferation via contributing biosynthesis of various essential molecules and energy production. Either glutamine anabolism or catabolism has a critical function in cancer metabolism depending on the complex nature and microenvironment of cancers. In this review, we focus on the role of GS in a variety of cancer types and microenvironments and highlight the mechanism of GS at the transcriptional and post-translational levels. Lastly, we discuss the therapeutic implications of targeting GS in cancer.
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Cognet, Guillaume, Colin Sheehan, Grace Croley, Lyndon Hu, and Alexander Muir. "Abstract PR14: Ex vivo models of pancreatic cancer that recapitulate the metabolic tumor microenvironment identify glycine as a chemoresistance-inducing oncometabolite." Cancer Research 84, no. 2_Supplement (January 16, 2024): PR14. http://dx.doi.org/10.1158/1538-7445.panca2023-pr14.
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Abstract Pancreatic adenocarcinoma (PDAC) tumors are poorly perfused due to intense desmoplasia and dysfunctional vasculature. This limited perfusion leads to abnormal availability of nutrients and metabolic substrates in the tumor microenvironment. To understand how microenvironmetnal nutrient availability impacts PDAC biology, we performed quantitative metabolomics of the interstitial fluid (the local perfusate) of PDAC tumors to comprehensively characterize nutrient availability in the PDAC microenvironment. We have used this information to develop Tumor Interstitial Fluid Medium (TIFM), a cell culture medium that contains nutrient levels representative of the PDAC microenvironment, enabling the study of PDAC biology under physiological nutrition. By transcriptomic analysis, we show that PDAC cells cultured in TIFM, compared to standard ex vivo models, adopt a cellular state more similar to PDAC cells in tumors, identifying TME nutrient availability as a key microenvironmental factor regulating PDAC biology in vivo. Given that PDAC cells in TIFM adopt an in vivo-like cell state, we next asked if PDAC cells in TIFM would exhibit phenotypes that PDAC cells primarily exhibit in vivo, such as resistance to chemotherapeutic treatment. We found that TIFM culture dramatically increases the resistance of PDAC cells to chemotherapeutic challenge. As TIFM is chemically defined, we systemically screened microenvironmental nutrient cues to identify those triggering therapy resistance. We found that glycine, an amino acid that accumulates to high levels in the PDAC microenvironment, was necessary and sufficient to cause PDAC therapy resistance. Glycine, at the concentrations found in the PDAC microenvironment, has been found to broadly cytoprotective by inhibiting cell death elicited by diverse cellular stresses. In mechanistic experiments, we similarly find that microenvironmental glycine does not prevent chemotherapeutic damage of PDAC cells but blocks cell death in response to this damage. Thus, we propose glycine is a novel oncometabolite that PDAC tumors accumulate, enabling them to cope with diverse stresses, including chemotherapeutic challenge. Altogether, these data show that nutrient availability in the microenvironment is an important determinant of PDAC biology, and models incorporating tumor nutrition can enable mechanistic study of microenvironmentally-programmed PDAC phenotypes. Citation Format: Guillaume Cognet, Colin Sheehan, Grace Croley, Lyndon Hu, Alexander Muir. Ex vivo models of pancreatic cancer that recapitulate the metabolic tumor microenvironment identify glycine as a chemoresistance-inducing oncometabolite [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr PR14.
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Wieder, Robert. "Fibroblasts as Turned Agents in Cancer Progression." Cancers 15, no. 7 (March 28, 2023): 2014. http://dx.doi.org/10.3390/cancers15072014.
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Differentiated epithelial cells reside in the homeostatic microenvironment of the native organ stroma. The stroma supports their normal function, their G0 differentiated state, and their expansion/contraction through the various stages of the life cycle and physiologic functions of the host. When malignant transformation begins, the microenvironment tries to suppress and eliminate the transformed cells, while cancer cells, in turn, try to resist these suppressive efforts. The tumor microenvironment encompasses a large variety of cell types recruited by the tumor to perform different functions, among which fibroblasts are the most abundant. The dynamics of the mutual relationship change as the sides undertake an epic battle for control of the other. In the process, the cancer “wounds” the microenvironment through a variety of mechanisms and attracts distant mesenchymal stem cells to change their function from one attempting to suppress the cancer, to one that supports its growth, survival, and metastasis. Analogous reciprocal interactions occur as well between disseminated cancer cells and the metastatic microenvironment, where the microenvironment attempts to eliminate cancer cells or suppress their proliferation. However, the altered microenvironmental cells acquire novel characteristics that support malignant progression. Investigations have attempted to use these traits as targets of novel therapeutic approaches.
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Shalek, Alex K. "Abstract IA007: Does cancer cell state matter? Moving from DNA genotype to RNA phenotype-directed therapies in cancer." Cancer Research 82, no. 22_Supplement (November 15, 2022): IA007. http://dx.doi.org/10.1158/1538-7445.panca22-ia007.
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Abstract Recent advances in high throughput genomic sequencing technologies have led to a detailed understanding of the genetic alterations that underlie human tumors. However, evidence increasingly indicates that using mutations alone to assign therapies has its limitations, even for cancers with actionable mutational heterogeneity. The advent of single-cell genomic technologies has confirmed extensive mutational heterogeneity in human tumors but also revealed that the complexity of cancer extends to variation in cell transcriptional state. Deciphering whether transcriptional variation informs treatment response heterogeneity represents a new but poorly understood frontier in cancer therapeutics. In pancreatic ductal adenocarcinoma (PDAC), clinically relevant RNA expression states exist but our understanding of their drivers, stability, and relationship to therapeutic response is limited. To examine these attributes systematically, we profiled metastatic biopsies and matched organoid models at single-cell resolution. We identify a new intermediate PDAC transcriptional cell state and uncover distinct site- and state-specific tumor microenvironments. Moreover, we reveal strong organoid culture-specific biases in cancer cell transcriptional state representation and nominate critical factors missing from the ex vivo microenvironment. By adding back specific factors, we restore in vivo expression state heterogeneity and show plasticity in culture models, demonstrating that microenvironmental signals are critical regulators of cell state. Importantly, we prove that non-genetic modulation of cell state can significantly influence drug responses and uncover state-specific vulnerabilities. Our work provides a broadly applicable framework for mapping cell states across in vivo and ex vivo settings, identifying drivers of transcriptional plasticity, and manipulating cell state to target its associated vulnerabilities. Citation Format: Alex K. Shalek. Does cancer cell state matter? Moving from DNA genotype to RNA phenotype-directed therapies in cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr IA007.
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Ye, Jiaan, Longgang Cui, Xiaochen Zhao, and Guanghui Lan. "Comparing of pan-cancer tumor immune microenvironment." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e15100-e15100. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e15100.
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e15100 Background: Cancer treatment has entered the era of immune checkpoint inhibitors (ICI), but different tumors have different responses to ICI drugs. For example, non-small cell lung cancer and melanoma have higher response rates to ICIs than colorectal cancer and liver cancer patients. Previous studies have shown that tumor immune microenvironment have a great impact on the efficacy of ICI. Methods: This study retrospectively included pan-cancer patient specimens, using multiple fluorescent labeling immunohistochemistry to explore the differences in the immune microenvironment of different tumors. Shapiro-Wilk was used for normality test, and ANOVA or Kruskal Wallis test was used according to the results. Two-sided P < 0.05 was considered a significant difference. Results: The study included 308 patients, including 119 (38.6%) NSCLC patients, 72 (23.4%) Colorectal cancer patients, 51 (16.6%) Hepatobiliary cancer patients and 66 (21.4%) Others types of cancer patients. Among them, there was 192 (62.3%) Male, and 116 (37.7%) Female, and the median age was 57 (50-66). The proportion of CD8+ T cells and natural killer cell in tumor was statistically different. The proportion of CD8+ T cells in NSCLC, Colorectal cancer, Hepatobiliary cancer and others was 2.16%, 1%, 1.77% and 2.63%, p < 0.01; the proportion of natural killer cell was 16.44 %, 4.91%, 5.58% and 3.29%, p < 0.01. Conclusions: Different tumor types have different immune microenvironments. These results may provide valuable clues for future ICI trail design.
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Devarasetty, Mahesh, Samuel Herberg, Anthony Dominijanni, Ethan Willey-Shelkey, Aleksander Skardal, and Shay Soker. "Biofabricated tumor microenvironments for studying colorectal cancer in vitro and in vivo." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e14689-e14689. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e14689.
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e14689 Background: Microenvironmental mechanics have a tremendous effect on the progression, phenotype, and therapeutic response of cancer cells positioning it as a high-potential target for novel therapeutic development. Laboratory modeling of the microenvironment and its multitude of effects is imperative for developing new avenues of anti-cancer therapy that can target non-traditional vectors such as the extracellular matrix (ECM) and stromal cells. Researchers have developed in vitro models of the tumor microenvironment (TME) to meet this need. While in vitro modeling is an important step in therapeutic development, there are few studies that validate in vitro generated results to gold-standard in vivo models, and further, to patient-derived data. Previously, we have developed a model of the colorectal tumor microenvironment and found a connection between collagen ultrastructure and cancer cell phenotype. Using this characterized organoid model, we implant bioengineered TMEs into mice to track long-term growth and progression of cancer and compare our results to clinical biopsies. Methods: Tumor organoids are produced by combining stromal cells and type I collagen. Cancer cell spheroids are embedded into the organoid for long term observation. Organoids are either observed in vitro or implanted subcutaneously into mice for in vivo tracking. Results: Organoids retain structure and viability during long term culture in vitro and in vivo, and embedded cancer cells respond significantly differently depending on the architecture of the surrounding TME. Cancer cells assume a mesenchymal, invasive, and proliferative phenotype in unorganized TMEs, and revert to an epithelial phenotype in an ordered TME. In addition, analysis of biopsied tissue, across tumor grade, demonstrates a correlation between cancer cell phenotype and microenvironmental architecture. Conclusions: In all this is the first study to establish a connection between TME micro-structure and cancer cell phenotype consistently across three distinct research modalities. These results have the potential to pave the way for utilizing bioengineered microenvironmental models as therapeutic development platforms and for targeting TME micro-structure to control colorectal cancer cell progression.
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Golebiewska, Anna, Anne Dirkse, Thomas Buder, Yahaya A. Yabo, Arnaud Muller, Petr V. Nazarov, Rolf Bjerkvig, et al. "STEM-09. INTRINSIC TUMOR PLASTICITY IN GLIOBLASTOMA ALLOWS FOR RECREATION OF STEM LIKE-STATES AND EFFICIENT TUMOR CELL ADAPTATION TO NEW MICROENVIRONMENTS." Neuro-Oncology 21, Supplement_6 (November 2019): vi235. http://dx.doi.org/10.1093/neuonc/noz175.983.
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Abstract BACKGROUND Cellular heterogeneity is a hallmark of numerous cancer types, including Glioblastoma (GBM). Cancer stem cells (CSC) have been accounted for the generation of phenotypic heterogeneity and tumor progression in GBM. Recent data, however, suggest that CSCs may not represent a stable entity and intrinsic plasticity plays a key role in tumor adaptation to changing microenvironments. The question arises whether CSCs are a defined subpopulation of GBM or whether they represent a cellular state that any cancer cell can adopt. METHODS We interrogated intra-tumoral phenotypic heterogeneity at the single cell transcriptomic and proteomic level in GBM biopsies, patient-derived stem-like cultures and orthotopic xenografts (PDOXs). Tumor cell subpopulations, classified based on their expression of four proposed stem cell markers (CD133, CD15, A2B5 and CD44), were FACS isolated and functionally characterized under various microenvironmental conditions. Mathematical Markov modelling was applied to calculate state transitions. RESULTS GBM patient biopsies, PDOXs and stem-like cell cultures displayed remarkable stem cell-associated intra-tumoral heterogeneity. However independent of marker expression, all analysed tumor subpopulations carried stem-cell properties and recreated phenotypic heterogeneity. Mathematical modeling revealed a different propensity in reforming heterogeneity over time, which was independent of the proliferation index but linked to in vivo tumorigenic potential. Although GBM subpopulations varied in their potential to adapt to new environments, all were able to reach a steady state microenvironment-specific equilibrium. CONCLUSIONS Our results suggest that phenotypic heterogeneity in GBM results from intrinsic plasticity allowing tumor cells to adapt to changing microenvironmental conditions. Cellular states are non-hierarchical, reversible and occur via stochastic state transitions, striving towards a microenvironment-instructed equilibrium. Our data provides evidence that CSCs do not represent a defined clonal entity, but rather a cellular state determined by environmental conditions, which has implications for the design of treatment strategies targeting CSC-like states.
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Hassan, Ghmkin, Said M. Afify, Shiro Kitano, Akimasa Seno, Hiroko Ishii, Yucheng Shang, Michiya Matsusaki, and Masaharu Seno. "Cancer Stem Cell Microenvironment Models with Biomaterial Scaffolds In Vitro." Processes 9, no. 1 (December 28, 2020): 45. http://dx.doi.org/10.3390/pr9010045.
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Defined by its potential for self-renewal, differentiation and tumorigenicity, cancer stem cells (CSCs) are considered responsible for drug resistance and relapse. To understand the behavior of CSC, the effects of the microenvironment in each tissue are a matter of great concerns for scientists in cancer biology. However, there are many complicated obstacles in the mimicking the microenvironment of CSCs even with current advanced technology. In this context, novel biomaterials have widely been assessed as in vitro platforms for their ability to mimic cancer microenvironment. These efforts should be successful to identify and characterize various CSCs specific in each type of cancer. Therefore, extracellular matrix scaffolds made of biomaterial will modulate the interactions and facilitate the investigation of CSC associated with biological phenomena simplifying the complexity of the microenvironment. In this review, we summarize latest advances in biomaterial scaffolds, which are exploited to mimic CSC microenvironment, and their chemical and biological requirements with discussion. The discussion includes the possible effects on both cells in tumors and microenvironment to propose what the critical factors are in controlling the CSC microenvironment focusing the future investigation. Our insights on their availability in drug screening will also follow the discussion.
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Lau, Allison N., and Matthew G. Vander Heiden. "Metabolism in the Tumor Microenvironment." Annual Review of Cancer Biology 4, no. 1 (March 9, 2020): 17–40. http://dx.doi.org/10.1146/annurev-cancerbio-030419-033333.
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Experiments in culture systems where one cell type is provided with abundant nutrients and oxygen have been used to inform much of our understanding of cancer metabolism. However, many differences have been observed between the metabolism of tumors and the metabolism of cancer cells grown in monoculture. These differences reflect, at least in part, the presence of nonmalignant cells in the tumor microenvironment and the interactions between those cells and cancer cells. However, less is known about how the metabolism of various tumor stromal cell types differs from that of cancer cells, and how this difference might inform therapeutic targeting of metabolic pathways. Emerging data have identified both cooperative and competitive relationships between different cell types in a tumor, and this review examines how four abundant stromal cell types in the tumor microenvironment, fibroblasts, T cells, macrophages, and endothelial cells, contribute to the metabolism of tumors.
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Plzák, Jan, Jan Bouček, Veronika Bandúrová, Michal Kolář, Miluše Hradilová, Pavol Szabo, Lukáš Lacina, Martin Chovanec, and Karel Smetana. "The Head and Neck Squamous Cell Carcinoma Microenvironment as a Potential Target for Cancer Therapy." Cancers 11, no. 4 (March 28, 2019): 440. http://dx.doi.org/10.3390/cancers11040440.
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Similarly to other types of malignant tumours, the incidence of head and neck cancer is increasing globally. It is frequently associated with smoking and alcohol abuse, and in a broader sense also with prolonged exposure to these factors during ageing. A higher incidence of tumours observed in younger populations without a history of alcohol and tobacco abuse may be due to HPV infection. Malignant tumours form an intricate ecosystem of cancer cells, fibroblasts, blood/lymphatic capillaries and infiltrating immune cells. This dynamic system, the tumour microenvironment, has a significant impact on the biological properties of cancer cells. The microenvironment participates in the control of local aggressiveness of cancer cells, their growth, and their consequent migration to lymph nodes and distant organs during metastatic spread. In cancers originating from squamous epithelium, a similarity was demonstrated between the cancer microenvironment and healing wounds. In this review, we focus on the specificity of the microenvironment of head and neck cancer with emphasis on the mechanism of intercellular crosstalk manipulation for potential therapeutic application.