Abstract
Integrins contribute to cancer progression and aggressiveness by activating intracellular signal transduction pathways and transducing mechanical tension forces. Remarkably, these adhesion receptors share common signaling networks with receptor tyrosine kinases (RTKs) and support their oncogenic activity, thereby promoting cancer cell proliferation, survival and invasion. During the last decade, preclinical studies have revealed that integrins play an important role in resistance to therapies targeting RTKs and their downstream pathways. A remarkable feature of integrins is their wide-ranging interconnection with RTKs, which helps cancer cells to adapt and better survive therapeutic treatments. In this context, we should consider not only the integrins expressed in cancer cells but also those expressed in stromal cells, since these can mechanically increase the rigidity of the tumor microenvironment and confer resistance to treatment. This review presents some of these mechanisms and outlines new treatment options for improving the efficacy of therapies targeting RTK signaling.
Highlights
Many tumors initially respond to targeted therapies before resistance appears
Integrins cooperate with several receptor tyrosine kinases (RTKs), such as epidermal growth factor receptor (EGFR), c-Met, platelet-derived growth factor receptor (PDGFR), insulin-like growth factor receptor (IGFR) and vascular endothelial growth factor receptor (VEGFR)
As shown in this review, integrin interacts with several RTKs such as the HER family, c-Met, PDGFR
Summary
Many tumors initially respond to targeted therapies before resistance appears. The mechanisms that sustain tumor cells between initial response and disease progression are not well understood. RTK signaling pathways regulate cell growth, differentiation, metabolism and apoptosis in response to growth factor stimulation of cross-activation by co-receptors such as integrins. Integrins cooperate with several RTKs, such as epidermal growth factor receptor (EGFR), c-Met, platelet-derived growth factor receptor (PDGFR), insulin-like growth factor receptor (IGFR) and vascular endothelial growth factor receptor (VEGFR) This cooperation promotes solid tumor progression and aggressiveness as well as contributing to therapy resistance, be it to chemotherapy, radiotherapy or targeted therapy. Hypermethylation of miR-483-3p in resistant cells activates the β3-dependent FAK/Erk pathway to promote cell survival and EMT [20]. Forced expression of galectin-1 elevates β3 expression and activates the FAK/PI3K/Akt pathway to trigger EMT This is correlated with an increased resistance to sorafenib in galectin-1 expressing cells. Β1 integrin antagonists such as small molecules (ATN-161, JSM6427) or function-blocking antibodies (volociximab, OS2966) have been considered as potential therapeutic approaches [32]
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