Cancer Cell Fusion and Post-Hybrid Selection Process (PHSP).

Simple Summary: Aberrant fusion of somatic cells or fusion of neoplastic cells may represent one fundamental process among others eventually promoting tumor development. Fusion events are rare, and cancer hybrid cells are further processed in a post-hybrid selection process (PHSP). Although the PHSP-surviving cancer hybrid cells represent a small minority within the tumor tissue, their changed properties may provide a proliferation advantage, eventually overgrowing other cancer cells. These new properties can include cancer stem-cell features such as self-renewal, immune escape, and chemotherapy/necroptosis resistance. Moreover, PHSP-derived cancer hybrid cells can undergo tumor dormancy or contribute to epithelial-mesenchymal transition and enhanced formation of distal organ or tissue metastases. Accordingly, detection of cancer-cell fusions in vivo in a patient's tumor tissues is challenging, and subsequent therapeutic interventions against these processes remain to be elucidated. Fusion of cancer cells either with other cancer cells (homotypic fusion) in local vicinity of the tumor tissue or with other cell types (e.g., macrophages, cancer-associated fibroblasts (CAFs), mesenchymal stromal-/stem-like cells (MSC)) (heterotypic fusion) represents a rare event. Accordingly, the clinical relevance of cancer-cell fusion events appears questionable. However, enhanced tumor growth and/or development of certain metastases can originate from cancer-cell fusion. Formation of hybrid cells after cancer-cell fusion requires a post-hybrid selection process (PHSP) to cope with genomic instability of the parental nuclei and reorganize survival and metabolic functionality. The present review dissects mechanisms that contribute to a PHSP and resulting functional alterations of the cancer hybrids. Based upon new properties of cancer hybrid cells, the arising clinical consequences of the subsequent tumor heterogeneity after cancer-cell fusion represent a major therapeutic challenge. However, cellular partners during cancer-cell fusion such as MSC within the tumor microenvironment or MSC-derived exosomes may provide a suitable vehicle to specifically address and deliver anti-tumor cargo to cancer cells. [ABSTRACT FROM AUTHOR]