Cryptic collagen elements as signaling hubs in the regulation of tumor growth and metastasis

Abstract

Structural remodeling of the extracellular matrix is a well‐established process associated with tumor growth and metastasis. Tumor and stromal cells that compose the tumor mass function cooperatively to promote the malignant phenotype in part by physically interacting with intact and structurally altered matrix proteins. To this end, collagen represents the most abundant component of the extracellular matrix and is known to control the behavior of histologically distinct tumor types as well as a diversity of stromal cells. Although a significant molecular understanding has been established concerning how cellular interactions with intact collagen govern signaling pathways that control tumor progression, considerably less is known concerning how interactions with cryptic or hidden regions within remodeled collagen may selectively alter signaling cascades, or whether inhibition of these cryptic signaling pathways may represent clinically effective therapeutic strategies. Here, we review the emerging evidence concerning the possible mechanisms for the selective generation of cryptic or hidden elements within collagen and their potential cell surface receptors that may facilitate signal transduction. We discuss the concept that cellular communication links between cell surface receptors and these cryptic collagen elements may serve as functional signaling hubs that coordinate multiple signaling pathways operating within both tumor and stromal cells. Finally, we provide examples to help illustrate the possibility that direct targeting of these unique cryptic signaling hubs may lead to the development of more effective therapeutic strategies to control tumor growth and metastasis.

The Functional Role of Extracellular Matrix Proteins in Cancer

“…These fragments in turn can regulate a wide array of biological processes, including angiogenesis, cell migration, adhesion and differentiation as well as tumor growth and metastasis [ 323 ]. It was found that matrikines can originate from collagen [ 324 , 325 ], elastin [ 326 , 327 ], tenascin [ 328 , 329 ], fibronectin [ 330 , 331 ], laminins [ 332 ], decorin, thrombospondin and versican [ 333 ].…”

The Extracellular Matrix-Derived Biomarkers for Diagnosis, Prognosis, and Personalized Therapy of Malignant Tumors

“…The matricryptines are generated by the structural or enzymatic modification of ECM resulting in exposure of the biologically active and previously hidden ("cryptic") sites. It has been suggested recently that cryptic collagen elements serve as signaling hubs regulating tumor metastasis and growth (33). ECM may also evolve releasing biologically active substances, including matrikines, which may be used as "protein fingerprint" of cancer.…”

Matrix Metalloproteinase 10 Contributes to Choroidal Neovascularisation

“…The release of this sequestered VEGF regulates vascular patterning and can transform normal angiogenesis into a pathological process [ 29 ]. In addition to merely degrading the basement membrane, proteolytic cleavage of collagen type IV results in exposure of cryptic binding sites hidden in the triple helical structure that facilitates EC adhesion and migration and is required for angiogenesis in vivo [ 30 ]. Blocking these cryptic sites inhibits retinal angiogenesis in vivo [ 28 ].…”