Tumor Microenvironment

Cancer is a multifactorial Disorder caused by variations in multiple genes coupled with environmental risk factors. The genes involved in the carcinogenesis can be classified into several groups, including proto-oncogenes, tumor suppressor genes, genes involved in genome stability and cell migration. The accumulations of genetic changes lead to tumor mass and formation of new blood vessels to grow. The tumor is not a collection of single cells and has bilateral interactions with its environments. The tumor microenvironment (TME) has a similar function to stem cells niches that affect tumor progression and metastasis. The study of this environment is effective in diagnosis and treatment of cancer and provides valuable and new information for controlling tumor malignancy and risk assessment (1). This paper focuses on TME components and the molecular targets for cancer treatment. Investigating of TME by cellular and molecular profiles indicated that there are different types of cells in this environment that promote neoplastic changes and metastasis and protect the tumor from the immune system and lead to resistance to treatment (2). Among the different types of cells present in the TME, including parenchymal tumor, fibroblasts, epithelial and inflammatory cells, extracellular matrix and signaling molecules, blood and lymph vessels, the highest number of cells are fibroblasts. In the early stages of carcinogenesis, normal fibroblasts prevent tumor growth. The genetic changes of these cells, with the help of inflammatory agents, release the growth factors that directly inhibit tumor-stimulating cells or indirectly inhibit apoptosis by stimulating growth and inducing angiogenesis. Therefore, a complex system of interactions is created by the involvement of a variety of cellular factors and molecular signals (3,4). Within the TME infrastructure, there are interactions of tumor cells with extracellular matrix (ECM), tumor-associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), mesenchymal stem cells (MSCs) and endothelial cells (EC). These communications have been established with the help of chemokines, growth factors, matrix metalloprotezes (MMPs) and ECM proteins, that lead to migration, invasion to distant organs and metastasis (5). TME restores tissue and induces metabolic changes in the tumor by making changes in the stromal and immune cells. This remodeling in a TME is similar to around of scar surrounded by different cells (6). Based on tissue type’s cancers, more than 40% of the CAFs can be derived from bone marrow progenitors that are recruited to the growing TME. Although CAFs may also be derived of epithelial cancer cells or stained fibroblasts that differentiate into myofibroblasts. In epithelial tumors, fibroblasts, mainly through the secretion of growth factors and chemokines, led to an altered ECM, and increase signals of proliferation and metastasis, and ultimately lead to tumor progression (7). The ECM also accumulated a scaffold of inflammatory and immune cells, lymph and nerve arteries. In general, in the metastatic phenomenon, the invasive tumors should be able to move, to break up the extracellular matrix of the tissue, to form new blood vessels, to survive in the blood and to stabilize in a new tissue environment. In studies that have been conducted to understand how these capabilities are achieved in cancer cells, TME has been identified as critical to the development of this phenomenon. TME stabilizes invasion of tumor to distant organs via signals to stromal or non-malignant cells and activation of transcription of genes (8,9). Also, angiogenesis precursor cells that are recruited to TME under hypoxic conditions are associated with metastasis. Some studies have shown that miRNA molecules are the main regulator of this activity, leading to changes in fibroblasts in the TME. MiR-21, miR-31, miR-214 and miR-155 play an important role in differentiation of normal fibroblasts to CAF (10). Although miRNAs in TME have not yet been fully identified, some studies indicated that miRNAs produced by TME cells and specially CAFs affect on tumor growth (11). Musumeci and colleagues showed the role of miRNAs in TME in prostate cancer. Their study found that expression of miR-15a and miR-16 down-regulated in fibroblasts of TME in prostate cancer. MiRNAs target oncogenes such as Bcl-2 and WNT pathway components (12). Several strategies have been proposed to remodel TME components in cancer treatment (2). Blocking the recruitment and activation of stromal cells in TME is one of these molecular approaches. Based on this strategy, Avastin has been designed to treat clone and glioblastoma cancer. Some drugs also block the interaction between the TME cells with the tumor and angiogenesis, ECM and inflammatory compounds in TME. Siltuximab is a human anti-IL-6 antibody that inhibits the pathway of IL-6 / STAT3 in cancer cells and its therapeutic effects have been reported in xenografet models. The effect of this drug in the Phase II clinical trials in platinuim-resistant ovarian cancer is under survey. More accurate identification of gene networks and cell pathways will help us improve our understanding of the pathogenesis of cancer and the advancement of therapeutic approaches. Therefore, in addition to controlling the signaling pathway inside the tumor, it is also necessary to identify the TME. Although, despite the recognition of the importance of TME in carcinogenesis, due to the multiplicity of involved cells, the origin of molecular mutations in its components is still not fully detected and requires extensive research in this area