Fibrosis and cancer: A strained relationship

Abstract

Tumors are characterized by extracellular matrix (ECM) deposition, remodeling, and cross-linking that drive fibrosis to stiffen the stroma and promote malignancy. The stiffened stroma enhances tumor cell growth, survival and migration and drives a mesenchymal transition. A stiff ECM also induces angiogenesis, hypoxia and compromises anti-tumor immunity. Not surprisingly, tumor aggression and poor patient prognosis correlate with degree of tissue fibrosis and level of stromal stiffness. In this review, we discuss the reciprocal interplay between tumor cells, cancer associated fibroblasts (CAF), immune cells and ECM stiffness in malignant transformation and cancer aggression. We discuss CAF heterogeneity and describe its impact on tumor development and aggression focusing on the role of CAFs in engineering the fibrotic tumor stroma and tuning tumor cell tension and modulating the immune response. To illustrate the role of mechanoreciprocity in tumor evolution we summarize data from breast cancer and pancreatic ductal carcinoma (PDAC) studies, and finish by discussing emerging anti-fibrotic strategies aimed at treating cancer.

Keywords: CAF; Cancer; ECM; Fibrosis; Mechanoreciprocity.

Fig. 1.

Elastic moduli in healthy human tissues and tumors. Cells within a tissue interact with their ECM which is tuned to a specific elastic modulus (measured in Pa) that dictate the function of the tissue. The ECM in the brain, lung or breast is relatively soft (compliant; <100 Pa), whereas the ECM in tissues that are exposed to high mechanical loading such as skeletal muscle and bone are by comparison stiff (>100 kPa). Soft ECMs promote neural cell growth, survival and intercellular connections, and critically permits the expansion of lung alveoli and mammary epithelial cells associated with breathing and milk delivery. By contrast, stiff ECMs favor osteoblast cell differentiation and cardiac contractility function. Tumors are often fibrotic, and the ECM is stiffer than that found in a healthy tissue (~4–10 kPa), and this ECM stiffness induces cytoskeletal tension that perturbs tissue organization and function. Critically reducing cytoskeletal tension reverts the malignant phenotype of tumor cells and inhibiting ECM stiffening prevents malignant transformation.

Fig. 2.

ECM homeostasis in healthy tissues and tumors. The interstitial ECM is composed of collagens, glycoproteins including fibronectin and proteoglycans, and water. Cells ligate to the ECM through transmembrane bound receptors such as integrins, which activate intracellular signaling and induce cytoskeletal reorganization to modify cell growth, survival and motility. The process by which cells sense mechanical signals from their microenvironment and translate these into biochemical signals is termed mechanotransduction. Activated integrins in cells ligating a soft ECM, assemble nascent, dynamic adhesions. By contrast, cells ligating a stiff ECM assemble stable focal adhesions as the resistance here favors the unfolding of tension sensitive adhesion plaque proteins such as talin and vinculin, which interact and nucleate multiple proteins that either stimulate downstream biochemical signaling cascades or activate GTPases that induce actin cytoskeletal reorganization. In a fibrotic tumor, the production and remodeling of the ECM is disturbed. CAFs produce increased amounts of ECM, as well as growth factors and enzymes that induce its remodeling and post-translational cross-linking that stiffens and aligns its fibrils to increases its tensile properties, enhance its density and elevate the compressive force experienced by cells within the tissue.

Fig. 3.

Integrin-dependent mechanotransduction. Integrins exist in a resting, inactive state and can be activated by internal (inside-out activation) or external (outside-in activation) cues including extracellular force (outside-in) or actomyosin contractility or tension (inside-out). Integrin activation is mediated by conformational changes in the integrin ectodomain that shifts the integrin from a low- to a high-affinity ligand binding state. A sufficient force upon integrin engagement will trigger the force-dependent unfolding of talin to expose vinculin binding sites. Vinculin binding to talin promotes its unfolding and recruits a suite of adhesion plaque proteins including Src, paxillin, α-actinin, and FAK that trigger downstream signaling and initiate actin reorganization and RhoGTPase-mediated actomyosin contractility to drive focal adhesion maturation.

Fig. 4.

Tumor-associated mechanoreciprocity. A simplified schematic of mechanoreciprocity in breast cancer evolution. Breast ducts are composed of two epithelial linings: inner luminal epithelial cells and outer myoepithelial cells. Breast ducts reside in an ECM populated by fibroblasts, endothelial cells, pericytes, leukocytes, and adipocytes. In a healthy breast, the tension exerted between the epithelium and stroma maintains tensional homeostasis. In ductal carcinoma in situ (DCIS), neoplastic epithelial cells proliferate and fill the lumen of the duct, thereby increasing solid stress. Neoplastic cells secrete factors that activate CAFs in the stroma to synthesize, remodel and stiffen the interstitial stroma, which mechanically resists the expansion of the DCIS lesion. The neoplastic epithelium in DCIS lesions responds to these forces by increasing their actomyosin tension that drives the assembly of focal adhesions to potentiate growth factor-dependent PI3K and ERK signaling and increases tumor cell contractility. Through the combined activity of the contractile tumor epithelium and activated CAFs, the BM surrounding DCIS lesions is compromised, and the collagenous-rich interstitial stroma becomes aligned and perpendicularly reorganized to support the invasion of the transformed breast epithelium into the interstitial stroma.