Science Challenging the Somatic Mutation Theory: Concerns Regarding the Epithelial Mesenchymal Transition (EMT) as an Explanation for Metastasis
Metastasis involves the spread of tumor cells from a primary site to distant sites with continued relentless growth. Metastasis is responsible for about 90 percent of cancer deaths and is the most fearsome aspect of cancer. Stephen Paget first proposed that metastasis depends on cross-talk between selected cancer cells (the seeds) and specific microenvironments (the soil). His concept still holds true today, according to Dr. Isaiah Fidler, a leader in cancer metastasis (36).
The epithelial mesenchymal transition (EMT) is currently the dominant explanation for the origin of cancer metastasis and is based on the somatic mutation theory of cancer (SMT). According to the EMT, random somatic mutations cause normal columnar epithelial cells to transform into non-adherent mesenchymal cells. These mutated mesenchymal cells then invade through the local tissue, intravasate (enter) blood vessels, survive in the circulation, suppress the immune system, extravasate (leave) blood vessels, and establish growth at sites distant from the primary tumor. No explanation is provided for how tumor cells with deranged genomes and random mutations could metastasize in a non-random manner according to the seed-soil hypothesis. David Tarin also believes that the EMT is fiction, as it has never been observed in cancer pathological specimens (37).
Figure 1 illustrates the well-documented metastatic cascade. A key aspect of metastasis is the non-random manner by which the metastatic cancer cells invade distant organs and tissues, with lung, liver, and bone as some of the more preferred sites. The green cells shown in Figure 1 are the tumor cells.
Emerging evidence indicates that metastatic cancer cells arise following the fusion of cancer stem cells with macrophages. Macrophages are already mesenchymal cells and are capable of entering and exiting tissues. Recent studies from John Pawelek, Melissa Wong, and Ivan Shabo provide compelling evidence that metastatic cancer cells arise from fusion hybridization of cancer cells and macrophages (38-40). We suggested that the replacement of normal mitochondria with defective mitochondria in the fusion hybrids could link the fusion hybrid hypothesis to the mitochondrial metabolic theory of cancer (MMT) (41). The process is illustrated in Figure 2.
Figure 2 depicts the origin of metastatic cancer cells, wherein the fusion event creates rogue macrophage-type cells with the capacity to invade through local tissue, intravasate (enter) blood vessels, survive in the circulation, suppress the immune system, extravasate (leave) blood vessels, and finally establish growth at sites distant from the primary tumor. The fusion hybrid hypothesis linked with the MMT can better explain the origin of cancer metastasis than can the EMT.
It is important to note that the fusion hybrid hypothesis originated with the work of the German pathologist Otto Aichel in 1911 (42). Aichel actually saw macrophage-type cells fusing with cancer cells under the microscope, providing direct evidence for the fusion event. Interestingly, Theodor Boveri crafted his chromosome mutation theory based on Aichel’s findings, as Aichel also noted abnormal chromosomes in the fused hybrids. It is therefore remarkable that the results from a single observation of cancer tissue would lead eventually to two fundamentally different explanations for the origin of cancer metastasis.
Thomas N. Seyfried is professor of biology at Boston College. He received a doctorate in genetics and biochemistry from the University of Illinois—Urbana-Champaign in 1976. He did his undergraduate work at the University of New England, where he recently received the distinguished Alumni Achievement Award. He also holds a master’s degree in genetics from Illinois State University. Seyfried served with distinction in the United States Army’s 1st Cavalry Division during the Vietnam War and received numerous medals and commendations.
He was a postdoctoral fellow in the Department of Neurology at the Yale University School of Medicine and then served on the faculty as an assistant professor in neurology. Seyfried previously served as chair of the Scientific Advisory Committee for the National Tay-Sachs and Allied Diseases Association. He recently received a Lifetime Achievement Award from the Academy of Complementary and Integrative Medicine and the Uncompromising Science Award from the American College of Nutrition for his work on cancer.
He presently serves on several editorial boards, including those for Nutrition & Metabolism, Neurochemical Research, the Journal of Lipid Research, and ASN Neuro. Seyfried has over 180 peer-reviewed publications and is author of the book “Cancer as a Metabolic Disease: On the Origin, Management, and Prevention of Cancer” (Wiley Press).
Note: These references include those previously published in “Is Cancer a Genetic or Metabolic Disease? Part 1,” “Part 2” and “Part 3.”
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