Figure 3.

Fusion-hybrid hypothesis for cancer cell metastasis. According to the fusion hybrid hypothesis, metastatic cancer cells can arise following fusion-hybridization between neoplastic epithelial cells and myeloid cells (macrophages). The fusion hybrid hypothesis originated with the work of Aichel in 1911 and was expanded by the Pawelek and the Munzarova groups [105,128,129,130,131,132]. Macrophages are known to invade in situ carcinoma as if it were an unhealed wound [95,109,133]. This creates a protracted inflammatory microenvironment leading to fusion hybridization between the neoplastic epithelial cell and the mesenchymal macrophage. Mitochondrial damage becomes the driver for the neoplastic transformation of the epithelial cell and of the fusion hybrids. Inflammation damages mitochondria leading to enhanced fermentation and acidification of the microenvironment. The gradual replacement of normal macrophage mitochondria with dysfunctional mitochondria in the hybrid cell cytoplasm leads to rogue behavior in cells that naturally possess the capability to, (1) move through tissues, (2) suppress the immune system, (3) enter (intravasate), and to exit (extravasate) the circulation. In addition to explaining the “seed-soil” hypothesis of metastasis, the fusion hybrid hypothesis can also explain how metastatic cells can re-capitulate the epithelial characteristics of the primary tumor at secondary micro-metastatic growth sites [4,85]. Furthermore, this hypothesis can explain the phenomenon of mesenchymal epithelial transition without invoking a mutation suppression mechanism. See text for more details. Modified from [85,134].