Stem Cell Theory of Cancer: Implications for Translational Research from Bedside to Bench

Self Cite

Although immunotherapy has revolutionized cancer care, there is still an urgent need to enhance its efficacy and ensure its safety. A correct cancer theory and proper scientific method empower pertinent cancer research and enable effective and efficient drug versus therapy development for patient care. In this perspective, we revisit the concept of immune privilege in a cancer cell versus normal cell, as well as in a cancer stem cell versus normal stem cell. We re-examine whether effective immunotherapies are efficacious due to their anti-cancer and/or immune modulatory mechanisms. We reassess why checkpoint inhibitors (CPIs) are not equal. We reconsider whether one can attribute the utility of immunotherapy to specific cancer subtypes and its futility to certain tumor/immune compartments, components, and microenvironments. We propose ways and means to advance immunotherapy beyond CPIs by combining anti-PD1/L1 with various other treatment modalities according to an appropriate scientific theory, e.g., stem cell origin of cancer, and based on available clinical evidence, e.g., randomized clinical trials. We predict that a stem cell theory of cancer will facilitate the design of better and safer immunotherapy with improved selection of its use for the right patient with the right cancer type at the right time to optimize clinical benefits and minimize potential toxic effects and complications.

Section: Drug Vs Therapy Developmentmentioning

confidence: 99%

Stem Cell Origin of Cancer: Clinical Implications beyond Immunotherapy for Drug versus Therapy Development in Cancer Care

Tu,

Trikannad,

Vellanki

et al. 2024

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“…However, neither DCA nor 2DG appeared to be effective for the treatment of patients with cancer in two phase I clinical trials [32,33]. Unfortunately, what works in the laboratory often enough does not work in the clinic, especially when we operate under a false or faulty hypothesis about cancer's origins and metabolism and do not adopt or adhere to the proper scientific method [34].…”

Section: Glucosementioning

confidence: 99%

“…How and what do we learn from history so that we do not make the same mistakes and will have a greater chance of ensuring success rather than enduring failure in drug versus therapy development for cancer care [34]? We propose that having the right cancer theory about the origin and nature of cancer is imperative.…”

Section: Drug Vs Therapy Developmentmentioning

confidence: 99%

Stem Cell Theory of Cancer: Clinical Implications for Cellular Metabolism and Anti-Cancer Metabolomics

Tu,

Chen,

Singh

et al. 2024

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Although Otto Warburg may be right about the role of glycolysis versus OXPHOS in cancer metabolism, it remains unclear whether an altered metabolism is causative or correlative and is the main driver or a mere passenger in the pathogenesis of cancer. Currently, most of our successful treatments are designed to eliminate non-cancer stem cells (non-CSCs) such as differentiated cancer cells. When the treatments also happen to control CSCs or the stem-ness niche, it is often unintended, unexpected, or undetected for lack of a pertinent theory about the origin of cancer that clarifies whether cancer is a metabolic, genetic, or stem cell disease. Perhaps cellular context matters. After all, metabolic activity may be different in different cell types and their respective microenvironments—whether it is in a normal progenitor stem cell vs. progeny differentiated cell and whether it is in a malignant CSC vs. non-CSC. In this perspective, we re-examine different types of cellular metabolism, e.g., glycolytic vs. mitochondrial, of glucose, glutamine, arginine, and fatty acids in CSCs and non-CSCs. We revisit the Warburg effect, an obesity epidemic, the aspartame story, and a ketogenic diet. We propose that a pertinent scientific theory about the origin of cancer and of cancer metabolism influences the direction of cancer research as well as the design of drug versus therapy development in cancer care.

“…However, if it is mainly based on experimental evidence that generates, rather than tests, a specific scientific hypothesis, then it is inherently flawed and could be self-serving and self-fulfilling. It may be right for the wrong reasons [22].…”

Section: Neoantigensmentioning

confidence: 99%

“…Therefore, the very idea of a stem cell versus genetic origin of cancer suggests that the concept of neoantigens may be flawed. When we formulate an erroneous hypothesis based on faulty observations of nature regarding neoantigens, we may still perform exemplary experiments to test the false hypothesis and obtain convincing results to support the hypothesis [22,32]. However, the clinical reward, if any, derived from such "preclinical" and "translational" research, could be haphazard, erratic, and academic, and the clinical benefits, at best, would be coincidental, incremental, and marginal.…”

Section: Neoantigensmentioning

confidence: 99%

Stem Cell Origin of Cancer: Implications of Oncogenesis Recapitulating Embryogenesis in Cancer Care

Aydın

Maraboyina

et al. 2023

Self Cite

From this perspective, we wonder about the clinical implications of oncology recapturing ontogeny in the contexts of neoantigens, tumor biomarkers, and cancer targets. We ponder about the biological ramifications of finding remnants of mini-organs and residuals of tiny embryos in some tumors. We reminisce about classical experiments showing that the embryonic microenvironment possesses antitumorigenic properties. Ironically, a stem-ness niche—in the wrong place at the wrong time—is also an onco-niche. We marvel at the paradox of TGF-beta both as a tumor suppressor and a tumor promoter. We query about the dualism of EMT as a stem-ness trait engaged in both normal development and abnormal disease states, including various cancers. It is uncanny that during fetal development, proto-oncogenes wax, while tumor-suppressor genes wane. Similarly, during cancer development, proto-oncogenes awaken, while tumor-suppressor genes slumber. Importantly, targeting stem-like pathways has therapeutic implications because stem-ness may be the true driver, if not engine, of the malignant process. Furthermore, anti-stem-like activity elicits anti-cancer effects for a variety of cancers because stem-ness features may be a universal property of cancer. When a fetus survives and thrives despite immune surveillance and all the restraints of nature and the constraints of its niche, it is a perfect baby. Similarly, when a neoplasm survives and thrives in an otherwise healthy and immune-competent host, is it a perfect tumor? Therefore, a pertinent narrative of cancer depends on a proper perspective of cancer. If malignant cells are derived from stem cells, and both cells are intrinsically RB1 negative and TP53 null, do the absence of RB1 and loss of TP53 really matter in this whole narrative and an entirely different perspective of cancer?