Role of RGD-binding Integrins in ovarian cancer progression, metastasis and response to therapy

Abstract Integrins are transmembrane receptors that play a crucial role in cell adhesion and signaling by connecting the extracellular environment to the intracellular cytoskeleton. After binding with specific ligands in the extracellular matrix (ECM), integrins undergo conformational changes that transmit signals across the cell membrane. The integrin-mediated bidirectional signaling triggers various cellular responses, such as changes in cell shape, migration and proliferation. Irregular integrin expression and activity are closely linked to tumor initiation, angiogenesis, cell motility, invasion, and metastasis. Thus, understanding the intricate regulatory mechanism is essential for slowing cancer progression and preventing carcinogenesis. Among the four classes of integrins, the arginine-glycine-aspartic acid (RGD)-binding integrins stand out as the most crucial integrin receptor subfamily in cancer and its metastasis. Dysregulation of almost all RGD-binding integrins promotes ECM degradation in ovarian cancer, resulting in ovarian carcinoma progression and resistance to therapy. Preclinical studies have demonstrated that targeting these integrins with therapeutic antibodies and ligands, such as RGD-containing peptides and their derivatives, can enhance the precision of these therapeutic agents in treating ovarian cancer. Therefore, the development of novel therapeutic agents is essential for treating ovarian cancer. This review mainly discusses genes and their importance across different ovarian cancer subtypes, the involvement of RGD motif-containing ECM proteins in integrin-mediated signaling in ovarian carcinoma, ongoing, completed, partially completed, and unsuccessful clinical trials of therapeutic agents, as well as existing limitations and challenges, advancements made so far, potential strategies, and directions for future research in the field. Insight Box Integrin-mediated signaling regulates cell migration, proliferation and differentiation. Dysregulated integrin expression and activity promote tumor growth and dissemination. Thus, a proper understanding of this complex regulatory mechanism is essential to delay cancer progression and prevent carcinogenesis. Notably, integrins binding to RGD motifs play an important role in tumor initiation, evolution, and metastasis. Preclinical studies have demonstrated that therapeutic agents, such as antibodies and small molecules with RGD motifs, target RGD-binding integrins and disrupt their interactions with the ECM, thereby inhibiting ovarian cancer proliferation and migration. Altogether, this review highlights the potential of RGD-binding integrins in providing new insights into the progression and metastasis of ovarian cancer and how these integrins have been utilized to develop effective treatment plans.