The Interplay between Extracellular Matrix Remodeling and Cancer Therapeutics

Abstract

The extracellular matrix (ECM) is an abundant noncellular component of most solid tumors known to support tumor progression and metastasis. The interplay between the ECM and cancer therapeutics opens up new avenues in understanding cancer biology. While the ECM is known to protect the tumor from anticancer agents by serving as a biomechanical barrier, emerging studies show that various cancer therapies induce ECM remodeling, resulting in therapy resistance and tumor progression. This review discusses critical issues in this field including how the ECM influences treatment outcome, how cancer therapies affect ECM remodeling, and the challenges associated with targeting the ECM. Significance: The intricate relationship between the extracellular matrix (ECM) and cancer therapeutics reveals novel insights into tumor biology and its effective treatment. While the ECM may protect tumors from anti-cancer agents, recent research highlights the paradoxical role of therapy-induced ECM remodeling in promoting treatment resistance and tumor progression. This review explores the key aspects of the interplay between ECM and cancer therapeutics.

Figure 1.

Tumor ECM remodeling. A, Tumor lesion showing basement membrane composed of laminin, collagen IV, and other components such as nidogen, while interstitial matrix contains collagen I/III and various proteoglycans. Infiltrating immune cells, such as TAMs and TANs, produce cytokines and growth factors that activate CAFs. In turn, CAFs produce the majority of the interstitial ECM. Collagens undergo crosslinking by LOX or LOXL2 enzymes, produced primarily by TAMs and CAFs, turning the ECM into a stiffened structure. ECM components, such as HA (hyaluronan), a polysaccharide that is produced by both tumor cells and stromal cells, absorb water causing the ECM to swell and enhance IFP. (Created with BioRender.com.)

Figure 2.

Cellular reciprocity and cell–ECM interactions. Cancer-associated myofibroblasts (mCAF), educated by cancer cells, produce abundant ECM components and stiffen it via their contractility. CAFs also secrete cytokines (IL6, IL8, GM-CSF) that activate TAMs and TANs into profibrotic/immunosuppressive M2 and N2 type, which in turn secrete TGFβ and activate and maintain myCAFs, creating a self-amplifying feedforward loop. ECM molecules undergo remodeling and degradation by enzymes such as MMPs, a disintegrin and metalloproteinases (ADAM), elastase, and cathepsins, largely secreted by TAMs and TANs. (Created with BioRender.com.)

Figure 3.

ECM remodeling in metastasis. Cancer cells release LOX that induces ECM crosslinking, while they can also produce ECM themselves. After undergoing EMT, cancer cells attain a mesenchymal phenotype capable of invading through the basement membrane by secreting MMPs and migrating to distant organs to form metastasis. Cancer cells at the primary tumor secrete exosomes, known as EVs, which are enriched with ECM molecules, MMPs, and cytokines responsible for ECM remodeling. EVs can travel to distant sites (lung, liver, bone), release their contents, and help create the premetastatic niche. (Created with BioRender.com.)

Figure 4.

ECM remodeling contributes to therapy resistance. The illustration represents the mechanisms by which ECM remodeling affects therapy outcome. Biochemical signals are associated with stored factors within the ECM which can be released when the ECM undergoes remodeling. This includes ECM associated enzymes, e.g., MMPs, ADAMs and cathepsins which contribute to tumor invasion. In addition, growth factors such as VEGF, HGF, and matrikines contribute to cell signaling support tumor proliferation and growth. Physical modules also support resistance and aggressiveness through stiffness which supports cancer cell proliferation through the expression of integrins and focal adhesion molecules, as well as supporting cell invasion through mechanotranduction pathways. ECM stiffness leads to immunotherapy and chemotherapy resistance by restricting the perfusion of drugs and infiltration of immune cells to the tumor site; Interstitial fluid pressure (IFP) which compresses blood vessels and inhibits the ability of drugs to penetrate the tumor tissue. In addition, HA engages with CD44 to support cancer cell motility, invasion, and proliferation; and ECM architecture is altered via crosslinking enzymes, further supporting “wavy” collagen fibers. The wavy fibers support mechanical resistance contributing to cell-cell junction, tumor cell survival and growth. The less wavy collagen fibers contribute to cancer cell invasion, an effect associated with the secretion of ECM degrading enzymes. The figure was created with BioRender.com.

Figure 5.

Mechanisms of therapy-induced ECM remodeling. The illustration represents the mechanisms by which therapy contributes directly to ECM remodeling. Surgery induces LOX expression at the surgical site, which contributes to ECM remodeling in the lungs. In addition, surgery activates neutrophils to secrete ECM-remodeling enzymes, e.g., MMP9. Radiation affects macrophages and CAFs, which infiltrate tumors and secrete ECM-remodeling enzymes including MMP9, heparanase, and cathepsins. In addition, it also contributes to the secretion of TGFβ by macrophages, which in turn affects fibrosis. Chemotherapy activates CAFs, which then support ECM remodeling. Furthermore, in response to chemotherapy, T cells secrete LOX, which then supports ECM remodeling at the premetastatic sites e.g., lungs. Chemotherapy can also increase ROS, which affects the activity of ECM-remodeling enzymes. Studies have demonstrated that bone marrow-derived cells infiltrate tumors in response to chemotherapy and secrete MMP9, which contributes to EMT and the degradation of the basement membrane, therefore supporting metastasis. Antiangiogenic therapy inhibits VEGF, which then contributes to changes in the expression of HA. These effects support ECM stiffness and contribute to metastatic cell seeding. In addition, it was demonstrated that hypoxia due to antiangiogenic therapy supports the secretion of cathepsins from the tumor tissue, leading to the activation of MMP9 and contributing to ECM degradation to support metastasis. (Created with BioRender.com.)