The extracellular matrix modulates the hallmarks of cancer

Abstract

The extracellular matrix regulates tissue development and homeostasis, and its dysregulation contributes to neoplastic progression. The extracellular matrix serves not only as the scaffold upon which tissues are organized but provides critical biochemical and biomechanical cues that direct cell growth, survival, migration and differentiation and modulate vascular development and immune function. Thus, while genetic modifications in tumor cells undoubtedly initiate and drive malignancy, cancer progresses within a dynamically evolving extracellular matrix that modulates virtually every behavioral facet of the tumor cells and cancer-associated stromal cells. Hanahan and Weinberg defined the hallmarks of cancer to encompass key biological capabilities that are acquired and essential for the development, growth and dissemination of all human cancers. These capabilities include sustained proliferation, evasion of growth suppression, death resistance, replicative immortality, induced angiogenesis, initiation of invasion, dysregulation of cellular energetics, avoidance of immune destruction and chronic inflammation. Here, we argue that biophysical and biochemical cues from the tumor-associated extracellular matrix influence each of these cancer hallmarks and are therefore critical for malignancy. We suggest that the success of cancer prevention and therapy programs requires an intimate understanding of the reciprocal feedback between the evolving extracellular matrix, the tumor cells and its cancer-associated cellular stroma.

Keywords: ECM; hallmarks of cancer; mechanotransduction.

© 2014 The Authors.

Figures

Figure 1

Influences of ECM on the hallmarks of cancer From tumor initiation to metastasis, the ECM influences each of the classically defined and emerging hallmarks of cancer as first described by Hanahan and Weinberg in 2000 and amended in 2011. ECM molecules bind to cell surface receptors, which activates intracellular signaling pathways. ECM adhesion-induced signals through ERK and PI3K promote self-sufficient growth . FAK signaling inhibits growth suppressors p15 and p21 and limits the induction of apoptosis through p53 . ECM components and biophysical properties promote EMT induction and enhance pro-migratory pathways, particularly TGF-β and RhoA/Rac signaling . ECM stiffness also enhances angiogenesis and increases VEGF signaling in endothelial cells . At each phase of tumorigenesis, the ECM adapts to reinforce the progression of the disease through promotion of the hallmarks.

Figure 2

Effects of matrix rigidity on tumor progression Recent work from Mouw et al shows how matrix rigidity impacts on tumor progression. (A) Culturing MCF10a cells on stiff polyacrylamide gels in vitro promotes FAK phosphorylation and suppresses the levels of the tumor suppressor PTEN. In vivo inhibition of collagen cross-linking (LOX-i) in the polyoma middle T (PyMT) mouse model of breast cancer results in the opposite phenotype, with PTEN levels being increased feeding into a suppression of Akt activity. (B) These data suggest that the stiffening of the ECM works through focal adhesions to inhibit tumor suppressors and promote tumor progression.

Figure 3

Influences of ECM on the metastatic cascade Tumor cell dissemination and establishment of metastatic lesions are controlled by several stringent processes that include induction of an invasive phenotype, migration through the tissue parenchyma, intravasation into the bloodstream, survival in the circulation, followed by extravasation and growth and survival at a secondary organ site. Adhesion to the ECM regulates each of these stages of tumor metastasis.