Stromal Players In Carcinogenesis

Tumor cells alter the surrounding stroma and in turn, the stromal cells may promote cancer progression and invasion. This is carried out by stromal cell like carcinoma-associated fibroblasts (CAFs), tumor associated macrophages (TAMs), endothelial cells (ECs), leucocytes, and bone marrow derived cells. While none of these cells are themselves malignant, owing to their environment and owing to their interaction with each other and directly/indirectly with the cancer cell, they acquire an abnormal phenotype and altered function. In this review paper, we will discuss in detail the various cellular and molecular components of stromal environment, their effect on cancer cells, and aspects of targeting this environment for control of cancer. Introduction Cancer is the number one cause of death in the United States for people less than 75 years old. Every year, more than 11 million people are diagnosed with cancer throughout the world and it may likely increase to 16 million by 2020. In 2005, cancer accounted for 7.6 million deaths from a total of 58 million deaths worldwide 1 . As a result, a re-evaluation of our basic assumptions concerning the nature of cancer and how to better assess risk, prevent, and medically manage is a high priority 2 . Recent advances in tumor biology have revealed that a detailed analysis of the complex interactions of tumor cells with their adjacent microenvironment (tumor stroma) is mandatory in order to understand the various mechanisms involved in tumor growth and the development of metastasis 3 . The tumor microenvironment is an evolving concept that defines the behavior of cancer not by the genetics of the tumor cells alone, but by the surrounding milieu that the tumor cells need for survival, growth, proliferation and metastasis 4 . The stroma consists of a compilation of cells, including fibroblasts/ myofibroblasts, glial, epithelial, fat, immune, vascular, smooth muscle, and immune cells along with the extracellular matrix (ECM) and extracellular molecules. While none of these cells are themselves malignant, due to their environment, their interactions with each other, and directly or indirectly STROMAL PLAYERS IN CARCINOGENESIS 3(2); 2017 91 Journal Of Applied Dental and Medical Sciences 3(2);2017 with the cancer cells, they acquire an abnormal phenotype and altered function. This abnormal interplay consisting of cell–cell contact and active molecular crosstalk further drives the cancer stroma phenotype, and may result in permanent alterations in cell function 5 . CELLS OF THE STROMA Cells within the stroma include fibroblasts, vascular, glial, smooth muscle, epithelial, and fat cells, and cells of the immune system. The most widely studied to date are the fibroblasts, immune cells, and the vascular cells, which we will focus on in this review 5 . Fibroblasts In normal tissue, fibroblasts are the predominant cell type in the connective tissue stroma and are the primary producers of the non-cellular scaffolds— the extracellular matrix (ECM). Fibroblasts are responsible for the deposition of the fibrillar ECM— type I, type III, and type V collagen and fibronectin— and contribute to the formation of the basement membrane by secreting type IV collagen and laminin.5 Quiescent fibroblasts undergo activation and become myofibroblasts during wound healing and fibrosis where both conditions share the requirement for tissue remodeling, as originally described by Giulio Gabbiani in 1971 6 . CANCER-ASSOCIATED FIBROBLASTS (CAFs) These cancer-associated fibroblasts (CAFs) are functionally and phenotypically distinct from normal fibroblasts that are in the same tissue but not in the tumor environment. CAFs directly stimulate tumor cell proliferation by contributing various growth factors, hormones and cytokines 7 . CAFs associated with incipient neoplasia exhibit a pro ‐ inflammatory signature, leading them mainly to over express SDF‐1, IL‐6 and IL‐1b, as well as to recruit proangiogenic macrophages and promote tumor growth 8 . Immune cells Monocytes/macrophages, neutrophils, and lymphocytes are recruited to and reside in the tumor stroma 5 . Macrophages exhibit an array of diverse functions that depend on factors encountered in their microenvironment. Their distinct effector phenotypes can be considered as a spectrum ranging from pro‐ inflammatory or host defense (M1), to anti ‐ inflammatory or regulatory (M2) phenotype. The relative balance of macrophage subsets is likely to STROMAL PLAYERS IN CARCINOGENESIS 3(2); 2017 92 Journal Of Applied Dental and Medical Sciences 3(2);2017 influence disease 9 . M1 and M2 polarized macrophages display a number of distinct features 10 . TUMOR-ASSOCIATED MACROPHAGES (TAM) Origin and accumulation of TAMs is by (1) Tumor ‐ derived chemo attractant, later identified as chemokine ligand ‐ 2(CCL2) ‐ which plays a role in their recruitment 11 (2) Molecules such as VEGF, PDGF, TGF‐β and M ‐ CSF are chemotactic for monocytes/ macrophages and also promote macrophage survival and differentiation (primarily M ‐