Role of Horizontal Gene Transfer in Cancer Progression

Abstract

Different forms of programmed cell death are known to happen at different stages in the course of normal development as well as during the life of healthy adult organisms to maintain physiologic homeostasis. Cell death causes the release into the surrounding environment of nucleic acids, proteins, and other macromolecules that can be discharged as free entities or incorporated into vesicles derived from intracellular membranes, including nuclear fragments, or from the cell membrane. Nucleic acids (DNA, RNA, non-coding RNAs) can be taken up by neighboring or distant cells and may promote in them significant changes in fundamental biological processes such as stress-response, gene expression, proliferation, differentiation, secretory patterns, substrate attachment, and many other functions. In the context of cancer progression, once tumors reach a certain size, prior to the establishment of a tumor-associated vasculature system, cancer cells in the inner portion of the tumor mass are subjected to stress conditions (e.g., hypoxia, acidic pH, limited nutrient availability), which in many cases result in cell death, with the consequent release of cellular malignancy-promoting materials (e.g., oncogenes, oncogenic miRNAs, and others) that, when taken up by normal cells, can promote their malignant transformation. In addition to such form of cell death-associated horizontal gene transfer, cancer cells have been shown to be particularly proficient at releasing cell membrane-derived vesicles, most frequently of the exosome type, carrying a variety of cancer-promoting cellular constituents. Exosomes are used by the tumor cells to shuttle reciprocal signals to stromal cells proximal to the tumors to favor the creation of a more favorable environment for cancer growth or to transport oncogenic molecules to remote destinations where they contribute to create a pro-metastatic niche in healthy tissues. In addition, exosome-mediated horizontal gene transfer has been shown to contribute to provide and spread resistance in response to diverse anticancer therapies. This review will summarize our current knowledge on the contribution of horizontal gene transfer from circulating cell-free nucleic acids (CNAs) or from exosome-encapsulated materials to the various stages of human tumor progression.