The concept of dedifferentiation and reprogramming of mature somatic cells holds much promise for the three-front “war” against tissue damage, cancer, and aging. It was hoped that reprogramming human somatic cells into the induced pluripotent state, along with the use of embryonic stem cells, would transform regenerative medicine. However, despite global efforts, clinical applications remain a distant dream, due to associated factors such as genomic instability, tumorigenicity, immunogenicity, and heterogeneity. Meanwhile, the expression of embryonic (pluripotent) markers in multiple cancers has baffled the scientific community, and it has been suggested that somatic cells dedifferentiate and “reprogram” into the pluripotent state in vivo to initiate cancer. It has also been suggested that aging can be reversed by partial reprogramming in vivo. However, better methods are needed; using vectors or Yamanaka factors in vivo, for example, is dangerous, and many potential anti-aging therapies carry the same risks as those using induced pluripotent cells, as described above. The present perspective examines the potential of endogenous, pluripotent very small embryonic-like stem cells (VSELs). These cells are naturally present in multiple tissues; they routinely replace diseased tissue and ensure regeneration to maintain life-long homeostasis, and they have the ability to differentiate into adult counterparts. Recent evidence suggests that cancers initiate due to the selective expansion of epigenetically altered VSELs and their blocked differentiation. Furthermore, VSEL numbers have been directly linked to lifespan in studies of long- and short-lived transgenic mice, and VSEL dysfunction has been found in the ovaries of aged mice. To conclude, a greater interest in VSELs, with their potential to address all three fronts of this war, could be the “light at the end of the tunnel.”

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e15024 Background: Prevailing somatic mutation theory (SMT) is mired with several paradoxes and still there is no clarity on how cancer initiates. No distinct pattern of somatic driver mutations specific to cancers affecting solid tissues has yet emerged even after massive NGS studies since 2007. Rather than cancer being a genetic disease, we postulate that endogenous, tissue-resident VSELs get transformed into CSCs to initiate cancer. Under normal conditions, VSELs along with tissue-specific progenitors work in a subtle manner to maintain life-long homeostasis in adult tissues. VSELs express steroid and gonadotropin hormone receptors, are directly vulnerable to environmental insults, and their dysfunction initiates various pathologies, including cancer. Recent mice studies have shown that environmental insults resulted in global hypomethylation, genomic instability and loss of imprinting (LOI) at IGF2/H19 loci that transformed quiescent VSELs into CSCs. Unlike VSELs, CSCs undergo excessive self-renewal, acquire bad-luck mutations during clonal expansion and oncogene activation to initiate cancers, and can also further mobilize to distant sites to cause metastasis. A 1000-sample clinical study based on OCT-4A expression by qRT-PCR suggested that CSCs that get mobilized from affected organs can serve as potential novel candidates for early detection of cancer through liquid biopsy. Methods: CSCs were enriched from the peripheral blood using our proprietary technology. They were enumerated by flow cytometry. VSELs undergo epigenetic changes and LOI to transform into CSCs. TaqMan based qRT-PCR was carried out to study OCT-4A and ALDH-1 positive CSCs and IGF2 expression to monitor LOI at the IGF2/H19 loci. LOI of IGF2 is commonly associated with initiation and also progression of multiple cancers and is also responsible for pushing VSELs out of quiescence and enter the cell cycle as CSCs. Results: Increased numbers of CSCs (epigenetically altered VSELs) were detected in peripheral blood samples of cancer subjects compared to normal subjects (p < 0.0001) by flow cytometry studies. The median absolute count of circulatory VSELs/CSCs was 190 per ml (IQR: 105-295) in normal subjects and 690 per ml (IQR: 370-1265) in cancer subjects. The qRT-PCR study conducted on 100 subjects showed increased expression of OCT-4A, IGF2 and ALDH1 genes in cancer compared to non-cancer subjects. Conclusions: Early detection of cancer by evaluating circulating tumor cells (CTCs) or tumor DNA (ctDNA) holds promise, but their scarce nature and mobilization in late stages only when tumor is > 3 mm in size, are major limitations for widespread translation. Circulating VSELs/CSCs in peripheral blood are evidently promising candidates to screen and classify subjects for cancer absence, likely risk, or presence.