Abstract
Radiation and drug resistance are significant challenges in the treatment of locally advanced, recurrent and metastatic breast cancer that contribute to mortality. Clinically, radiotherapy requires oxygen to generate cytotoxic free radicals that cause DNA damage and allow that damage to become fixed in the genome rather than repaired. However, approximately 40% of all breast cancers have hypoxic tumor microenvironments that render cancer cells significantly more resistant to irradiation. Hypoxic stimuli trigger changes in the cell death/survival pathway that lead to increased cellular radiation resistance. As a result, the development of noninvasive strategies to assess tumor hypoxia in breast cancer has recently received considerable attention. Exosomes are secreted nanovesicles that have roles in paracrine signaling during breast tumor progression, including tumor-stromal interactions, activation of proliferative pathways and immunosuppression. The recent development of protocols to isolate and purify exosomes, as well as advances in mass spectrometry-based proteomics have facilitated the comprehensive analysis of exosome content and function. Using these tools, studies have demonstrated that the proteome profiles of tumor-derived exosomes are indicative of the oxygenation status of patient tumors. They have also demonstrated that exosome signaling pathways are potentially targetable drivers of hypoxia-dependent intercellular signaling during tumorigenesis. This article provides an overview of how proteomic tools can be effectively used to characterize exosomes and elucidate fundamental signaling pathways and survival mechanisms underlying hypoxia-mediated radiation resistance in breast cancer.
Highlights
In the United States, breast cancer is the most common non-skin cancer and the second leading cause of cancer-related death in women
Our results demonstrated that exposure to hypoxia causes the loss of function of vacuolar protein sorting-associated protein VPS4B, which is involved in maintaining the fidelity of multivesicular body (MVB) maturation, resulting in increased breast cancer cell anchorage-independent growth and resistance to anti-EGFR, anti-MEK and genotoxicity induction treatment
It has been shown that the proteome profiles of tumor-derived exosomes are associated with the oxygenation status of patient tumors and that exosome signaling pathways are potentially targetable drivers of hypoxia-dependent intercellular signaling during tumorigenesis
Summary
In the United States, breast cancer is the most common non-skin cancer and the second leading cause of cancer-related death in women. Kucharzewska et al have demonstrated that the proteome and mRNA profiles of exosomes closely reflect the oxygenation status of donor glioma cells and patient tumors, and that exosomal signaling is a potentially targetable inducer of hypoxia-dependent intercellular signaling during tumor development [4]. For this reason, proteomic profiling of tumor exosomes circulating in cancer patient plasma or serum has the potential to provide functional diagnostic markers of disease without the invasiveness of biopsy procedures [25,26]. In this paper we will describe the role of hypoxia in breast carcinogenesis, basic exosome biology, and the potential for manipulating exosome-mediated intercellular signaling to increase the efficacy of breast cancer radiotherapy
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