The role of cancer-associated fibroblasts, solid stress and other microenvironmental factors in tumor progression and therapy resistance

Abstract

Tumors are not merely masses of neoplastic cells but complex tissues composed of cellular and noncellular elements. This review provides recent data on the main components of a dynamic system, such as carcinoma associated fibroblasts that change the extracellular matrix (ECM) topology, induce stemness and promote metastasis-initiating cells. Altered production and characteristics of collagen, hyaluronan and other ECM proteins induce increased matrix stiffness. Stiffness along with tumor growth-induced solid stress and increased interstitial fluid pressure contribute to tumor progression and therapy resistance. Second, the role of immune cells, cytokines and chemokines is outlined. We discuss other noncellular characteristics of the tumor microenvironment such as hypoxia and extracellular pH in relation to neoangiogenesis. Overall, full understanding of the events driving the interactions between tumor cells and their environment is of crucial importance in overcoming treatment resistance and improving patient outcome.

Keywords: Cancer associated fibroblasts; Interstitial fluid pressure; Solid stress; Therapy resistance; Tumor microenvironment.

Figure 1

Schematic of the biomechanical forces in the tumor microenvironment. As tumor cells proliferate they sequentially create new solid material (i.e. cells and matrix components) which generate radial and circumferential solid stresses. In the tumor center, circumferential and radial stresses are compressive while in the periphery, radial stress is compressive and circumferential stress is tensile (direction indicated with arrows). Compressive stresses in the tumor interior squeeze tumor components, including lymphatic and blood vessels (note compressed lumen of blood vessel and high density of cells and extracellular matrix in dark green). After the tumor is cut and the stresses are released, the tumor interior decompresses (note extended lumen of blood vessel, relaxed cells and extracellular matrix in light green). Reproduced and modified with permission from Prof. Rakesh K. Jain [55].