Tumor Stroma and Regulation of Cancer Development

Abstract

In the past 25 years, a majority of cancer studies have focused on examining functional consequences of activating and/or inactivating mutations in critical genes implicated in cell cycle control. These studies have taught us a great deal about the functions of oncogenes and tumor suppressor genes and the signaling pathways regulating cell proliferation and/or cell death. However, such studies have largely ignored the fact that cancers are heterogeneous cellular entities whose growth is dependent upon reciprocal interactions between genetically altered "initiated" cells and the dynamic microenvironment in which they live. This review highlights the aspects of cancer development that, like organogenesis during embryonic development and tissue repair in adult mammals, are regulated by interactions between epithelial cells, activated stromal cells, and soluble and insoluble components of the extracellular matrix.

Tumor-Secreted LOXL2 Activates Fibroblasts through FAK Signaling

“…Factors secreted from the tumor cells activate local fibroblasts, which in turn secrete increased levels of growth factors, chemokines, ECM proteins, and matrix remodeling enzymes to modify the tumor microenvironment and promote proliferation, survival, invasion, and metastasis of the tumor cells (5,(16)(17)(18). Fibroblasts sense changes in their microenvironment through integrins (19), and form focal adhesion complexes with intracellular molecules that engage the cytoplasmic tyrosine kinases, focal adhesion kinase (FAK) and Src, to activate multiple signaling pathways (20)(21)(22).…”

Microenvironmental regulation of metastasis

“…It is now well established that primary tumours are composed of a multitude of stromal cell types in addition to cancerous cells 26 . Among the stromal cell types that have been implicated in tumour promotion are endothelial cells, which comprise the blood and lymphatic circulatory systems, pericytes, fibroblasts and various BMDCs, including macrophages, neutrophils, mast cells, myeloid cell-derived suppressor cells (MDSCs) and mesenchymal stem cells (MSCs) (FIG.…”

The biology of personalized cancer medicine: Facing individual complexities underlying hallmark capabilities

“…Cancer‐associated fibroblasts represent another important stromal cell population in most tumor types (Kalluri and Zeisberg, 2006; Tlsty and Coussens, 2006; Pietras and Ostman, 2010). While often referred to generically as CAFs, there are evidently a number of distinctive fibroblastic cell types encompassed by this designation, including recruited myofibroblasts expressing smooth muscle actin, and activated (‘reactive’) resident tissue fibroblasts (Pietras and Ostman, 2010).…”

“…While often referred to generically as CAFs, there are evidently a number of distinctive fibroblastic cell types encompassed by this designation, including recruited myofibroblasts expressing smooth muscle actin, and activated (‘reactive’) resident tissue fibroblasts (Pietras and Ostman, 2010). The functionality of CAFs has been demonstrated for example by co‐injection of CAFs together with tumor cells, which enhances tumor growth by promoting ECM synthesis and stiffening, inducing angiogenesis, and recruiting growth‐promoting inflammatory cells such as macrophages (Erez et al., 2010; Kalluri and Zeisberg, 2006; Orimo et al., 2005; Tlsty and Coussens, 2006). CAFs are particularly abundant in certain human cancers, such as PDAC, and in various carcinomas at advanced stages of progression (e.g., breast and colorectal cancer).…”