Do PGCCs in Solid Tumors Appear Due to Treatment-related Stress or Clonal Expansion of CSCs that Survive Oncotherapy?

Dedifferentiation of epithelial cells during epithelial-mesenchymal transition (EMT) results in circulating tumor cells (CTCs) that are mobilized singly or in clusters in association with blood cells and results in metastasis. However, lineage tracing studies have failed to delineate any role of EMT during metastasis. Research is also focused on polyploid giant cancer cells (PGCCs) in solid tumors which appear in response to oncotherapy-related stress for their role in metastasis. But how to explain PGCCs role in metastatic tumors in treatment-naïve patients? Studies done using mouse models and clinical samples suggest that cancer initiates due to dysfunctions of tissue-resident, pluripotent very small embryonic-like stem cells (VSELs). VSELs are the most primitive and pluripotent stem cells that exist at top of cellular hierarchy in multiple tissues. They are normally quiescent and undergo asymmetrical cell divisions to give rise to two cells of different sizes and fates including smaller cells to self-renew and bigger tissue-specific progenitors. Progenitors undergo symmetrical cell divisions and clonal expansion (rapid proliferation, endoduplication with incomplete cytokinesis) to form giant cells that further breakdown and differentiate into tissue-specific cell types. Oncotherapy destroys actively dividing cells, but CSCs survive. We hypothesize that excessive self-renewal and clonal expansion of cancer stem cells (CSCs, dysfunctional VSELs) result in multinucleated giant cells (PGCCs) that accumulate as further differentiation into tissue-specific cell types is blocked in cancerous conditions. PGCCS are being reported by multiple groups whereas CSCs remain elusive due to small size and low abundance and actually contribute to both cancer initiation and metastasis.