Extracellular Matrices and Cancer-Associated Fibroblasts: Targets for Cancer Diagnosis and Therapy?

Abstract

Solid cancer progression is dictated by neoplastic cell features and pro-tumoral crosstalks with their microenvironment. Stroma modifications, such as fibroblast activation into cancer-associated fibroblasts (CAFs) and extracellular matrix (ECM) remodeling, are now recognized as critical events for cancer progression and as potential therapeutic or diagnostic targets. The recent appreciation of the key, complex and multiple roles of the ECM in cancer and of the CAF diversity, has revolutionized the field and raised innovative but challenging questions. Here, we rapidly present CAF heterogeneity in link with their specific ECM remodeling features observed in cancer, before developing each of the impacts of such ECM modifications on tumor progression (survival, angiogenesis, pre-metastatic niche, chemoresistance, etc.), and on patient prognosis. Finally, based on preclinical studies and recent results obtained from clinical trials, we highlight key mechanisms or proteins that are, or may be, used as potential therapeutic or diagnostic targets, and we report and discuss benefits, disappointments, or even failures, of recently reported stroma-targeting strategies.

Organ on Chip Technology to Model Cancer Growth and Metastasis

“…Unlike noncancerous myofibroblasts, CAFs do not revert to their inactivated state and overexpress the platelet-derived growth factor (PDGF) receptor-β, which successively supports their own proliferation [ 8 , 47 ]. Due to their important role in enhancing tumor growth, CAFs are currently taken into account in many studies as primary targets of anticancer therapeutic approaches [ 48 ].…”

“…Solid tumors contain large extracellular matrix deposits that constitute up to 60% of the tumor mass. Large collagen deposits, together with a high percentage of fibroblast infiltration, result in desmoplasia, which is strongly linked to poor patient prognosis [ 48 ].…”

Mechanisms and Clinical Significance of Tumor Lymphatic Invasion

“…Another important factor influencing the migratory behavior of tissue-infiltrating cancer cells is the extracellular matrix (ECM) which is often abnormal and/or undergoing constant remodeling within the tumor mass and the tumor periphery due to the activity of various cell types present within the TME, such as cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), and cancer cells themselves. For an in-depth discussion of this topic, we refer the reader to several comprehensive, recent review articles [61][62][63].…”

Extracellular Vesicles in Lung Cancer Metastasis and Their Clinical Applications

“…Pro-angiogenetic factors, such as VEGF-A and proinflammatory cytokines, including TNFα and TGFβ, are released by cancer cells [ 205 , 207 , 208 , 209 ]. Cancer-associated fibroblasts modify the extracellular matrix by secreting metalloproteases and promoting the proliferation and invasion of tumor cells [ 210 , 211 ]. Hematopoietic precursor cells have been shown to express VEGFR and can colonize the pre-metastatic lung sites before the CTCs arrive [ 212 , 213 ].…”