Caveolae-Associated Molecules, Tumor Stroma, and Cancer Drug Resistance: Current Findings and Future Perspectives

SIMPLE SUMMARY: Cell membranes contain small invaginations called caveolae. They are a specialized lipid domain and orchestrate cellular signaling events, mechanoprotection, and lipid homeostasis. Formation of the caveolae depends on two classes of proteins, the caveolins and cavins, which form large complexes that allow their self-assembly into caveolae. Loss of either of these two proteins leads to distortion of the caveolae structure and disruption of many physiological processes that affect diseases of the muscle, metabolic states governing lipids, and the glucose balance as well as cancers. In cancers, the expression of caveolins and cavins is heterogenous, and they undergo alterations both in the tumors and the surrounding tumor microenvironment stromal cells. Remarkably, their expression and function has been associated with resistance to many cancer drugs. Here, we summarize the current knowledge of the resistance mechanisms and how this knowledge could be applied into the clinic in future. ABSTRACT: The discovery of small, “cave-like” invaginations at the plasma membrane, called caveola, has opened up a new and exciting research area in health and diseases revolving around this cellular ultrastructure. Caveolae are rich in cholesterol and orchestrate cellular signaling events. Within caveola, the caveola-associated proteins, caveolins and cavins, are critical components for the formation of these lipid rafts, their dynamics, and cellular pathophysiology. Their alterations underlie human diseases such as lipodystrophy, muscular dystrophy, cardiovascular disease, and diabetes. The expression of caveolins and cavins is modulated in tumors and in tumor stroma, and their alterations are connected with cancer progression and treatment resistance. To date, although substantial breakthroughs in cancer drug development have been made, drug resistance remains a problem leading to treatment failures and challenging translation and bench-to-bedside research. Here, we summarize the current progress in understanding cancer drug resistance in the context of caveola-associated molecules and tumor stroma and discuss how we can potentially design therapeutic avenues to target these molecules in order to overcome treatment resistance.