Stem Cell Theory of Cancer: Rude Awakening or Bad Dream from Cancer Dormancy?

Simple Summary The stem cell theory of cancer predicates that both normal and cancer stem cells can be induced into or released from dormancy depending on their multipotential constraints and microenvironment restraints. A unified theory of cancer predicts that even though genetic makeup in cancer dormancy maybe pivotal, cellular context must be paramount. After all, both normal stem cells and cancer stem cells proliferate and differentiate. They can be stationary and migratory. They can be static and dynamic. Importantly, gonadal germ cells are prototype stem cells and germ cell tumor of the testis (TGCT) is a model stem cell cancer. In a TGCT and other cancers, we witness the many manifestations and myriad revelations of cancer dormancy in prolonged remissions, late relapses, second malignancies, and fulminant cancers. To be dormant or not depends on the origin and nature of both the cell and its niche. Similar to other cancer hallmarks, dormancy is ingrained with stemness, and stemness is embedded within dormancy. After all, cancer dormancy is dependent on multiple factors such as cell cycle arrest, metabolic inactivity, and the microenvironment. It is the net results and sum effects of a myriad of cellular interactions, interconnections, and interplays. When we unite all cancer networks and integrate all cancer hallmarks, we practice and preach a unified theory of cancer. From this perspective, we review cancer dormancy in the context of a stem cell theory of cancer. We revisit the seed and soil hypothesis of cancer. We reexamine its implications in both primary tumors and metastatic lesions. We reassess its roles in cell cycle arrest, metabolic inactivity, and stemness property. Cancer dormancy is particularly revealing when it informs us about the mysteries of late relapse, prolonged remission, and second malignancy. It is paradoxically rewarding when it delivers us the promises and power of cancer prevention and maintenance therapy in patient care.