Insidious Changes in Stromal Matrix Fuel Cancer Progression

Abstract

Reciprocal interactions between tumor and stromal cells propel cancer progression and metastasis. An understanding of the complex contributions of the tumor stroma to cancer progression necessitates a careful examination of the extracellular matrix (ECM), which is largely synthesized and modulated by Cancer Associated Fibroblasts (CAFs). This structurally supportive meshwork serves as a signaling scaffold for a myriad of biological processes and responses favoring tumor progression. The ECM is a repository for growth factors and cytokines that promote tumor growth, proliferation, and metastasis through diverse interactions with soluble and insoluble ECM components. Growth factors activated by proteases are involved in the initiation of cell signaling pathways essential to invasion and survival. Various transmembrane proteins produced by the cancer stroma bind the collagen and fibronectin-rich matrix to induce proliferation, adhesion and migration of cancer cells, as well as protease activation. Integrins are critical liaisons between tumor cells and the surrounding stroma, and with their mechano-sensing ability induce cell signaling pathways associated with contractility and migration. Proteoglycans also bind and interact with various matrix proteins in the tumor microenvironment to promote cancer progression. Together, these components function to mediate crosstalk between tumor cells and fibroblasts ultimately to promote tumor survival and metastasis. These stromal factors, which may be expressed differentially according to cancer stage, have prognostic utility and potential. In this review, we examine changes in the ECM of cancer associated fibroblasts induced through carcinogenesis, and the implications of these changes on cancer progression.

Transient mechanical strain promotes the maturation of invadopodia and enhances cancer cell invasion in vitro

“…These mechanical factors include changes in the structure and mechanics of the whole tissue, as well as local biophysical changes in the geometry and topology of the extracellular matrix (ECM). Much of the early focus has been on the obvious changes in stiffness, since the stroma surrounding most tumors often becomes more rigid and dense due to an enrichment of collagen type I and fibronectin (Miles and Sikes, 2014;Pickup et al, 2014). This increase in rigidity leads to an increase in tumor cell proliferation, migration and invasion (Alexander et al, 2008;Charras and Sahai, 2014;Jerrell and Parekh, 2014;Kostic et al, 2009;Parekh and Weaver, 2009;Tilghman et al, 2010;Ulrich et al, 2009;Umesh et al, 2014).…”

Stroma Liquid Biopsy™ - A Proteomic Model of the Systemic Response to Cancer

“…As stromal cells within the microenvironments of tumors are genetically stable compared to tumor cells, their derivative proteomes may offer attractive therapeutic targets to help manage an often incurable disease and prolong survival [1,2]. As such, any and all multi-parametric profiles that can help to monitor and stratify cancer patients for individual clinical situations will become highly desirable [3,4].We hypothesized that because of tumor vasculature, changes in the serum proteome might associate to the dynamic composition of the tumor-associated stromal microenvironments, and can thus be monitored by blood tests. We can now envision such measurements contributing to a Stroma Liquid Biopsy™ and we adopt this new term here to differentiate our model from previous liquid biopsies.…”

Stroma as an Active Player in the Development of the Tumor Microenvironment

“…Both ECM components (including several distinct families of molecules including glycosaminoglycans and proteoglycans, collagens and non-collagenous glycoproteins), as well as vessels and nerves, comprise a complex scaffold. Within the spaces of this structure and along the fibers and elements composing the scaffold, cells can migrate, meet and directly interact [9][10][11][12][13]. Consequently, it is important to consider the physical characteristics of the tumor microenvironment structure.…”

“…This is especially true for effector cells of the immune system which require direct intercellular contact for immune priming, as well as for cytotoxic responses. Accordingly, tissue remodeling and changes in the architecture and density of the fibrous stroma may either help or hamper anticancer immune responses in the tumor microenvironment [12,13]. Insights from the study of ECM in wound repair and connective tissue illnesses show the value of a "stromal" approach to immunobiology of the tumor microenvironment.…”