The Influence of the Cancer Microenvironment on the Process of Metastasis (original) (raw)
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Journal of Cancer Metastasis and Treatment , 2019
Breast cancer (BC) is the leading cause of cancer-related deaths in women worldwide. However, the majority of cancer mortalities can be attributed to cancer cell metastasis to distal organs/tissues rather than the primary tumor mass itself. The microenvironment surrounding the main tumor mass, as well as its final migration destination, plays a crucial role in the survival, growth, proliferation, and progression of BC. Intercellular stromal cells and components of the microenvironment surrounding a tumor comprise a nurturing cubicle that provides a communication network of cross-talk and signaling between the tumor cells and the extracellular matrix (ECM) and interstitial cells. This network connection enables the tumor cells to engage in metastatic-associated activities such as cell adhesion, invasiveness, mobility, migration, cell shape change, cell-to-cell contact, and basement membrane degradation. An untapped therapeutic approach that might disable the communication network between cancer and stromal cells could possibly aid in providing this unmet need in treating metastatic disease. The intravenous administration of select protein-derived peptides to patients might have the potential to occupy, saturate, and block receptors and binding proteins at the interstitial/ECM communication interface with tumors.
International Journal of Molecular Sciences
Breast cancer-associated fibroblasts (BCAFs), the most abundant non-cancer stromal cells of the breast tumor microenvironment (TME), dramatically sustain breast cancer (BC) progression by interacting with BC cells. BCAFs, as well as myofibroblasts, display an up regulation of activation and inflammation markers represented by α-smooth muscle actin (α-SMA) and cyclooxygenase 2 (COX-2). BCAF aggregates have been identified in the peripheral blood of metastatic BC patients. We generated an in vitro stromal model consisting of human primary BCAFs grown as monolayers or 3D cell aggregates, namely spheroids and reverted BCAFs, obtained from BCAF spheroids reverted to 2D cell adhesion growth after 216 h of 3D culture. We firstly evaluated the state of activation and inflammation and the mesenchymal status of the BCAF monolayers, BCAF spheroids and reverted BCAFs. Then, we analyzed the MCF-7 cell viability and migration following treatment with conditioned media from the different BCAF cult...
Tumor microenvironment of metastasis and risk of distant metastasis of breast cancer
Journal of the National Cancer Institute, 2014
Tumor microenvironment of metastasis (TMEM), consisting of direct contact between a macrophage, an endothelial cell, and a tumor cell, has been associated with metastasis in both rodent mammary tumors and human breast cancer. We prospectively examined the association between TMEM score and risk of distant metastasis and compared risk associated with TMEM score with that associated with IHC4. We conducted a case-control study nested within a cohort of 3760 patients with invasive ductal breast carcinoma diagnosed between 1980 and 2000 and followed through 2010. Case patients were women who developed a subsequent distant metastasis; control subjects were matched (1:1) on age at and calendar year of primary diagnosis. TMEM was assessed by triple immunostain and IHC4 by standard methods; slides were read by pathologists blinded to outcome. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression, adjusted for clinical variables. A Receiver Operating C...
Tumor microenvironment: a main actor in the metastasis process
Clinical & Experimental Metastasis, 2012
Over recent decades, various studies have argued that the metastatic tissue microenvironment is fully controlled by the intrinsic properties of the cancer cells (growth, motility and invasion, angiogenesis, extracellular matrix remodeling, immune escape) and additional cells types. Overall, the extrinsic factors and determinants mediate the contribution of the host microenvironment to metastasis formation. The tumor microenvironment carries out these functions by secretion of molecules that can influence and modulate its phenotype, making these complex interactions the basis for support for the progression of a cancer. Here, we undertake a summary of the ''state of the art'' of the functions and actions of these cells, as the main actors in the promotion of the formation of the microenvironment of the metastatic niche, and the associated network of interactions. The unraveling of the relationships between tumorigenic cells and their microenvironment represents an important issue for the development of new therapeutic agents that can fight both initiation and recurrence of cancer.
The Multifaceted Nature of Tumor Microenvironment in Breast Carcinomas
Pathobiology
Heterogeneity in breast carcinomas can be appreciated at various levels, from morphology to molecular alterations, and there are well-known genotypic-phenotypic correlations. Clinical decision-making is strictly focused on the evaluation of tumor cells and is based on the assessment of hormone receptors and of the HER2 status, by means of a combination of immunohistochemical and in situ hybridization techniques. The tumor microenvironment (TME) also shows a multifaceted nature stemming from the different actors populating the intratumoral and the peritumoral stroma of breast carcinomas. Of note, we have now evidence that tumor-infiltrating lymphocytes (TILs) are clinically meaningful as their quantification in the intratumoral stroma strongly correlates with good prognosis, in particular in triple-negative and HER2-positive breast cancer patients. Nevertheless, TILs are just one of the many actors orchestrating the complexity of the TME, which is populated by immune and nonimmune cells (cancer-associated fibroblasts, cancer-associated adipocytes), as well as non-cellular components such as chemical inflammation mediators. In this review article we will overview the main features of the distinct cell compartments by discussing (i) the potential impact the TME may have on the prognostic stratification of breast cancers and (ii) the possible predictive value of some markers in the context of immunotherapy in light of the recent results of phase III studies in advanced and early triple-negative breast cancer patients.
Cancers
Cancer cells metastasize from primary tumors to regional lymph nodes and distant sites via the lymphatic and blood vascular systems, respectively. Our prior work has demonstrated that in primary breast tumors, cancer cells utilize a three-cell complex (known as tumor microenvironment of metastasis, or TMEM) composed of a perivascular macrophage, a tumor cell expressing high levels of the actin-regulatory protein mammalian enabled (Mena), and an endothelial cell as functional “doorways” for hematogenous dissemination. Here, we studied a well-annotated case–control cohort of human invasive ductal carcinoma of the breast and metastatic lymph nodes from a separate breast cancer cohort. We demonstrate that in primary breast tumors, blood vessels are always present within tumor cell nests (TCNs) and tumor-associated stroma (TAS), while lymphatic vessels are only occasionally present in TCN and TAS. Furthermore, TMEM doorways not only exist in primary tumors as previously reported but also...
Stroma as an Active Player in the Development of the Tumor Microenvironment
Cancer Microenvironment, 2014
The stroma is a considerable part of the tumor microenvironment. Because of its complexity, it can influence both cancer and immune cells in their behavior and cross-talk. Aside from soluble products released by non-cancer and cancer cells, extracellular matrix components have been increasingly recognized as more than just minor players in the constitution, development and regulation of the tumor microenvironment. The variations in the connective scaffold architecture, induced by transforming growth factor beta, lysyl oxidase and metalloproteinase activity, create different conditions of ECM density and stiffness. They exert broad effects on immune cells (e.g. physical barriers, modulation by release of stored TGF-β1), mesenchymal cells (transition to myofibroblasts), epithelial cells (epithelial-to-mesenchymal transition), cancer cells (progression to metastatic phenotype) and stem cells (activation of differentiation addressed by the microenvironment characteristics). Physiological mechanisms of the wound healing process, as well as mechanisms of fibrosis in some chronic pathologies, closely recall aspects of cancer deregulated biology. Their elucidation can provide a better understanding of tumor microenvironment immunobiology. In the following short review, we will focus on some aspects of the fibrous stroma to highlight its active participation in the tumor microenvironment constitution, tumor progression and the local immunological network.
2021
Introduction: Tumor microenvironment plays a significant role in tumor progression. Tumor stroma is one of the strongest modifiers of tumor cell response, cancer behavior, and cancer progression. This study aimed to investigate the correlation of matrix metalloproteinase-9 (MMP-9) expression and tumor-stroma ratio (TSR) with standard clinicopathological parameters in different molecular subtypes of breast cancer.Methods: Ninety biopsy samples of primary breast cancer diagnosed at the Department of Pathology, School of Medicine, Sarajevo, were selected for this study. The molecular subtype was determined based on the immunohistochemical expression of estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, and Ki-67. Stromal and tumoral MMP-9 immunohistochemical expression and the TSR were determined for each tumor.Results: Tumoral MMP-9 expression correlated positively with the presence of lymphovascular invasion (p= 0.016). TSR showed significant associat...
Gene expression profiling of the tumor microenvironment during breast cancer progression
Breast Cancer …, 2009
The importance of the tumor microenvironment in breast cancer has been increasingly recognized. Critical molecular changes in the tumor stroma accompanying cancer progression, however, remain largely unknown. We conducted a comparative analysis of global gene expression changes in the stromal and epithelial compartments during breast cancer progression from normal to preinvasive to invasive ductal carcinoma.