Stem Cell Origin of Cancer: Clinical Implications for Cancer Immunity and Immunotherapy

APC mutation is the main driving mechanism of CRC development and leads to constitutively activated WNT signaling, overpopulation of ALDH+ stem cells (SCs), and incomplete differentiation. We previously reported that retinoic acid (RA) receptors are selectively expressed in ALDH+ SCs, which provides a way to target cancer SCs with retinoids to induce differentiation. Hypotheses: A functional link exists between the WNT and RA pathways, and APC mutation generates a WNT:RA imbalance that decreases retinoid-induced differentiation and increases ALDH+ SCs. Accordingly, to restore parity in WNT:RA signaling, we induce wt-APC expression in APC-mutant CRC cells, and we assess the ability of all-trans retinoic acid (ATRA) to induce differentiation. We found that ATRA increased expression of the WNT target gene, CYP26A1, and inducing wt-APC reduced this expression by 50%. Thus, the RA and WNT pathways crosstalk to modulate CYP26A1, which metabolizes retinoids. Moreover, inducing wt-APC augments ATRA-induced cell differentiation by: (i) decreasing cell proliferation; (ii) suppressing ALDH1A1 expression; (iii) decreasing ALDH+ SCs; and (iv) increasing neuroendocrine cell differentiation. A novel CYP26A1-based network that links WNT and RA signaling was also identified by NanoString profiling/bioinformatics analysis. Furthermore, CYP26A1 inhibitors sensitized CRC cells to the anti-proliferative effect of drugs that downregulate WNT signaling. Notably, in wt-APC-CRCs, decreased CYP26A1 improved patient survival. These findings have strong potential for clinical translation.

Section: Discussionmentioning

confidence: 85%

CYP26A1 Links WNT and Retinoic Acid Signaling: A Target to Differentiate ALDH+ Stem Cells in APC-Mutant CRC

Facey,

Hunsu,

Zhang

et al. 2024

“…When we talk about immunotherapy, it is essential for us to think about the origin and nature of immune privilege in both cancer and normal cells [ 9 ]. According to a stem cell theory of cancer, similarities in intrinsic immune privilege between cancer and normal stem cells may predicate the success or implicate any failure of immunotherapy in cancer care.…”

Section: Immune Privilegementioning

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

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.

“…Subsequently, Stevens [11] and Pierce [12,13] demonstrated a stem cell origin in germ cell tumors. A stem cell theory of cancer embraces all aspects of cancer hallmarks, including the complexities of cancer metabolism and the vagaries of genetic instability [14,15]. Importantly, the idea that cancer is a stem cell disease rises above and beyond the metabolome and the genome-it envisions a unified theory of cancer that views cancer in a different cellular perspective and metabolism in the proper epigenomic context [14,15].…”

Section: Brief Historymentioning

confidence: 99%

“…There is evidence suggesting that CSCs (a small subpopulation of cells within tumors capable of self-renewal, differentiation, and tumorigenicity when transplanted into an animal host) mimic or mirror NSCs, because the former may be related to, if not derived from, the latter [14,15]. Consequently, they share many stem-ness and stem-like properties, including metastatic potential, intra-tumoral heterogeneity, cancer dormancy, drug resistance, and cellular metabolism [16][17][18][19][20].…”

Section: Stem Cell Originmentioning

confidence: 99%

“…In addition, the activity of NNMT is tightly linked to the maintenance of nicotinamide adenine dinucleotide (NAD + ), which modulates multiple enzymatic reactions that affect redox metabolism, mitochondrial functions, stem-ness properties, autophagic processes, cellular stress, ion homeostasis, and the circadian rhythm [51,52]. This is reminiscent of a complex metabolic network in need of a unified conceptual framework, as premised in this perspective [14,15]. Importantly, NNMT may be a potential biomarker and therapeutic target for cancer diagnosis and treatment [53][54][55].…”

Section: S-adenosyl-l-methionine (Sam)mentioning

confidence: 99%

See 1 more Smart Citation

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

Tu,

Chen,

Singh

et al. 2024

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.