Intrinsic signalling factors associated with cancer cell-cell fusion

Abstract

Cellular fusion e.g. between cancer cells and normal cells represents a stepwise process that is tightly regulated. During a pre-hybrid preparation program somatic cells and/or cancer cells are promoted to a pro-fusogenic state as a prerequisite to prepare a fusion process. A pro-fusogenic state requires significant changes including restructure of the cytoskeleton, e.g., by the formation of F-actin. Moreover, distinct plasma membrane lipids such as phosphatidylserine play an important role during cell fusion. In addition, the expression of distinct fusogenic factors such as syncytins and corresponding receptors are of fundamental importance to enable cellular mergers. Subsequent hybrid formation and fusion are followed by a post-hybrid selection process. Fusion among normal cells is important and often required during organismal development. Cancer cells fusion appears more rarely and is associated with the generation of new cancer hybrid cell populations. These cancer hybrid cells contribute to an elevated tumour plasticity by altered metastatic behaviour, changes in therapeutic and apoptotic responses, and even in the formation of cancer stem/ initiating cells. While many parts within this multi-step cascade are still poorly understood, this review article predominantly focusses on the intracellular necessities for fusion among cancer cells or with other cell populations of the tumour microenvironment.

Altered Phenotypes of Breast Epithelial × Breast Cancer Hybrids after ZEB1 Knock-Out

“…While invasion data of the M13HS-2 and -8 tumor hybrids suited well to the assumption, that tumor hybrids often exhibit novel properties, such as an enhanced metastatic capacity [30,38,39,73,74], it remains unclear why the invasive capacity of M13HS-2 ZEB1-KO cells was not diminished, but rather comparable to M13HS-2 wildtype cells. ZEB1 is a well-known inducer of EMT and high ZEB1 levels are associated with a higher invasive capacity of cancer cells, whereas invasion is impaired upon ZEB1 knock-down [4,75,76].…”

“…Cell-cell fusion itself represents a biological phenomenon that is mandatory for several physiological processes, such as fertilization, placentation, myogenesis, osteoclastogenesis, and wound healing/tissue regeneration [29][30][31][32][33][34][35][36][37]. Additionally, cell-cell fusion takes also place in pathophysiological conditions, such as infection of host cells with enveloped viruses and cancer [38][39][40][41][42][43][44][45]. With regard to cancer, it is known that cancer cells could fuse with normal cells, such as macrophages, fibroblasts, and stem cells, thereby giving rise to tumor hybrids possessing novel properties, such as immune escape, an increased drug resistance, an enhanced metastatic capacity, and prospective CSC properties [38][39][40][41][42][43][44][45][46][47][48][49].…”

“…Additionally, cell-cell fusion takes also place in pathophysiological conditions, such as infection of host cells with enveloped viruses and cancer [38][39][40][41][42][43][44][45]. With regard to cancer, it is known that cancer cells could fuse with normal cells, such as macrophages, fibroblasts, and stem cells, thereby giving rise to tumor hybrids possessing novel properties, such as immune escape, an increased drug resistance, an enhanced metastatic capacity, and prospective CSC properties [38][39][40][41][42][43][44][45][46][47][48][49]. Albeit both the spontaneous fusion frequencies of cancer cells/normal cells and the overall survival rates of tumor hybrids appear to be rather low (up to 1% each), mathematical modeling revealed that fusion-mediated recombination can have a profound impact on accelerated diversification of tumor cell populations and an increasing intratumoral heterogeneity [50].…”

How Much Do You Fuse? A Comparison of Cell Fusion Assays in a Breast Cancer Model

“…The next step is the attachment of two or more pro-fusogenic cells to each other, which is catalyzed by so-called fusogenic proteins in order to overcome the energetic repulsion of the cells, followed by hemi fusion of the membranes, fusion pore opening and the complete fusion of the cells [ 4 , 22 ]. The time-dependent expression of these fusogenic proteins additionally regulates fusogenic triggers and cell fusion in an intrinsic manner, for example, during fertilization, the formation of the placenta or myogenesis [ 23 ]. One example of a fusogenic protein is the human endogenous retroviral (HERV) protein Syncytin-1, which can bind to alanine serine cysteine transporter 2 (ASCT2) on a neighboring cell and brings them in close proximity for fusion.…”

Entering, Linked with the Sphinx: Lysophosphatidic Acids Everywhere, All at Once, in the Oral System and Cancer

“…Dittmar and Hass (2023) [ 24 ] examined cancer cell fusion, a pathological process that increases malignancy and lowers survival; as with most tumors, metastases are the main cause of death in >90% of cancer cases [ 25 , 26 ]. Therefore, especially if cancer cells fuse with mesenchymal stem cells (MSC) and there is a subsequent post-hybrid selection process (PHSP), this significantly boosts metastatic ability [ 27 , 28 ].…”