Proteins Regulating Microvesicle Biogenesis and Multidrug Resistance in Cancer

Abstract

Microvesicles (MV) are emerging as important mediators of intercellular communication. While MVs are important signaling vectors for many physiological processes, they are also implicated in cancer pathology and progression. Cellular activation is perhaps the most widely reported initiator of MV biogenesis, however, the precise mechanism remains undefined. Uncovering the proteins involved in regulating MV biogenesis is of interest given their role in the dissemination of deleterious cancer traits. MVs shed from drug‐resistant cancer cells transfer multidrug resistance (MDR) proteins to drug‐sensitive cells and confer the MDR phenotype in a matter of hours. MDR is attributed to the overexpression of ABC transporters, primarily P‐glycoprotein and MRP1. Their expression and functionality is dependent on a number of proteins. In particular, FERM domain proteins have been implicated in supporting the functionality of efflux transporters in drug‐resistant cells and in recipient cells during intercellular transfer by vesicles. Herein, the most recent research on the proteins involved in MV biogenesis and in the dissemination of MV‐mediated MDR are discussed. Attention is drawn to unanswered questions in the literature that may prove to be of benefit in ongoing efforts to improve clinical response to chemotherapy and circumventing MDR.

A liquid biopsy to detect multidrug resistance and disease burden in multiple myeloma

“…Increased PS has been correlated with tumour aggressivity 36 and its presence on MPs has been shown to be associated with neovascularization through interactions with vascular endothelial cells 37 . PS is also an MP marker, its presence arising from the loss of phospholipid asymmetry during MP biogenesis 18 . PS + MP counts hence also coincide with increased tumour burden.…”

“…Microparticles (MPs) are a subset of extracellular vesicles (0.1−1 µm in diameter) released from the plasma membranes of most cell types 15 . MPs differ from other extracellular vesicles by virtue of their size, biogenesis and cargo [16][17][18] . Circulating MPs have been detected systemically for many cancers including MM, breast, prostate, and lung cancer [19][20][21][22][23][24] .…”

Novel Intrinsic Mechanisms of Active Drug Extrusion at the Blood-Brain Barrier: Potential Targets for Enhancing Drug Delivery to the Brain?

“…This report added another dimension to the ways that cells can acquire a particular cell surface protein-mediated phenotype, such as multidrug resistance [ 100 ]. Since then, numerous studies have confirmed the finding of Levchenko et al [ 108 ], showing that intercellular Pgp transfer occurs in different cancer cell lines, and exploring mechanisms involved in this transfer [ 69 , 109 , 110 , 111 , 112 ].…”

Potential role of exosomes in cancer therapy

“…At present, the major therapeutic methods of cancer include surgery, chemotherapy, radiotherapy, and immunotherapy . Resistance to treatment with anticancer agents remains a major clinical problem, resulting in anticancer treatment failure . The problem of chemoresistance is complex, mainly because several factors are involved, such as overexpression of drug efflux pumps, drug inactivation, DNA repair mechanisms, and alterations or mutations in the drug target .…”

“…2 Resistance to treatment with anticancer agents remains a major clinical problem, resulting in anticancer treatment failure. 3 The problem of chemoresistance is complex, mainly because several factors are involved, such as overexpression of drug efflux pumps, drug inactivation, DNA repair mechanisms, and alterations or mutations in the drug target. 4 Radioresistance is caused by a variety of factors that include the intrinsic biology that arises from the aberrant genetic makeup of tumor cells, the extensive heterogeneity of brain tumors, and the tumor microenvironment, which fosters and supports conditions that limit the response to radiation.…”