The extracellular matrix alteration, implication in modulation of drug resistance mechanism: friends or foes?

Abstract

The extracellular matrix (ECM) is an important component of the tumor microenvironment (TME), having several important roles related to the hallmarks of cancer. In cancer, multiple components of the ECM have been shown to be altered. Although most of these alterations are represented by the increased or decreased quantity of the ECM components, changes regarding the functional alteration of a particular ECM component or of the ECM as a whole have been described. These alterations can be induced by the cancer cells directly or by the TME cells, with cancer-associated fibroblasts being of particular interest in this regard. Because the ECM has this wide array of functions in the tumor, preclinical and clinical studies have assessed the possibility of targeting the ECM, with some of them showing encouraging results. In the present review, we will highlight the most relevant ECM components presenting a comprehensive description of their physical, cellular and molecular properties which can alter the therapy response of the tumor cells. Lastly, some evidences regarding important biological processes were discussed, offering a more detailed understanding of how to modulate altered signalling pathways and to counteract drug resistance mechanisms in tumor cells.

Cancer-Associated Fibroblasts in Hepatocellular Carcinoma and Cholangiocarcinoma

“… 66 Many solid tumors, such as HCC and CCA, express large amounts of ECM components, including fibrillar collagen, laminin, proteoglycans, and fibronectin, which mostly come from activated CAFs. 67 Santamato et al 68 reported that activated HSC could produce and secrete the ECM component laminin-5, which contributes the migration and invasion of HCC cells via the mitogen-activated protein kinase ERK kinase/extracellular-signal-regulated kinase pathway. Increased and reorganized ECM protein secreted by CAFs reinforce the deposition of fibrillar collagen, thereby mechanically giving rise to ECM stiffening and promoting tumor cell proliferation and invasion.…”

Collagen-Based Biomimetic Systems to Study the Biophysical Tumour Microenvironment

“…Owing to the importance of the biophysical microenvironment of the tumour ECM in regulating various aspects of cancer cell behaviour including, migration, proliferation and drug resistance [ 28 , 100 ], CDMs represent physiologically relevant and more controllable models for fundamental research on cancer as well as for screening or testing antitumoral drugs. Several matrices derived from either tumour cells or non-tumour cells have been proposed for a variety of tumours, including oral cancer [ 101 ], breast cancer [ 102 , 103 ], myeloma bone disease [ 104 ], ovarian cancer and colorectal cancer [ 105 , 106 ].…”

PLOD2 promotes colorectal cancer progression by stabilizing USP15 to activate the AKT/mTOR signaling pathway

“…Therefore, it is essential to clarify the molecular mechanisms behind the development of CRC to investigate novel molecular targets for early diagnosis and treatment. Collagen deposition and crosslinking happen frequently in malignant tumors and increase the risk of tumorigenesis and invasion, allowing individual tumor cells to migrate out along radially aligned fibers 5–7 …”

“…Collagen deposition and crosslinking happen frequently in malignant tumors and increase the risk of tumorigenesis and invasion, allowing individual tumor cells to migrate out along radially aligned fibers. [5][6][7] Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) is located on human chromosome 3 (3q24). The PLOD family has…”