Stem Cell Origin of Cancers: Biological and Clinical Implications of a Unified Theory of Cancer

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Pathophysiology".

Deadline for manuscript submissions: closed (5 December 2023) | Viewed by 8986

Special Issue Editors


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Guest Editor
Division of Hematology/Oncology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
Interests: genitourinary malignancies; cancer stem cells; intratumoral heterogeneity

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Guest Editor
Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Interests: prostate cancer; urology

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Guest Editor
Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Interests: prostate cancer; testicular cancer; targeted prostate cancer therapy; MIS testicular cancer surgery

Special Issue Information

Dear Colleagues,

We are pleased to invite you to contribute to a Special Issue in Cancers related to research pertaining to the stem cell origin of cancers.

 Nowadays, the conventional wisdom is that genetic mutations cause cancer. We seek driver mutations amidst a plethora of passenger mutations. However, it is doubtful that driver mutations drive several cancer hallmarks, including metastasis and heterogeneity. 

There is also a prevailing sentiment that precision medicine is key to effective and safe cancer treatment. However, when we face and deal with cancers that have complex genetic makeup and dynamic epigenetic potential, the reality is more fluid than stable, mutable than predictable—the exact opposite of precision.

Another popular belief is that defective immunity enables cancer. We would like to manipulate and harness the immune system for our singular therapeutic purposes. However, it seems that many patients have an intact immune system, and most cancers are innately immune privileged.

Therefore, we need novel ideas to account for this reality of cancer. We need a stem cell origin—a unified theory—that encompasses and embraces the varied myriad aspects (e.g., genomic, epigenomic, immunological) of cancer.

This Special Issue aims to inspire research and provide data to convince the skeptics and convert the cynics. Hopefully, Mark Twain was right when he said that the person “with a new idea is a crank, until the idea succeeds”. This Special Issue aims to clarify current narratives and perspectives on cancer. The idea that cancer is a stem cell disease and that the stem cell origin of cancer may be the unified theory of cancers have broad biological ramifications and immense clinical implications. It affects how we connect disparate scientific disciplines and how we pursue drug versus therapy developments.

In this Special Issue, original research articles and reviews are welcome. Research areas may include (but not limited to) the following: cancer stem cells, stem-ness or stem-like biomarkers, metabolism, and microenvironment.

We look forward to receiving your contributions.

Dr. Shi-Ming Tu
Dr. Louis L. Pisters
Prof. Dr. John F. Ward
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cancer stem cells
  • cancer-initiating cell
  • progenitor cell
  • epithelial–Mesenchymal transition
  • pluripotency
  • plasticity
  • heterogeneity
  • embryogenesis
  • stem-like
  • stem-ness

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Published Papers (5 papers)

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Research

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12 pages, 4713 KiB  
Article
Dual Targeting of EZH2 Degradation and EGFR/HER2 Inhibition for Enhanced Efficacy against Burkitt’s Lymphoma
by Se Been Kim, Chae-Eun Yang, Yurim Jeong, Minseo Yu, Wan-Su Choi, Jung-Yeon Lim and Youngwoo Jeon
Cancers 2023, 15(18), 4472; https://doi.org/10.3390/cancers15184472 - 8 Sep 2023
Cited by 1 | Viewed by 1298
Abstract
EZH2, a histone methyltransferase, contributes significantly to cancer cell survival and proliferation. Although various EZH2 inhibitors have demonstrated promise in treating lymphoma, they have not fully managed to curb lymphoma cell proliferation despite effective reduction of the H3K27me3 mark. We used MS1943, an [...] Read more.
EZH2, a histone methyltransferase, contributes significantly to cancer cell survival and proliferation. Although various EZH2 inhibitors have demonstrated promise in treating lymphoma, they have not fully managed to curb lymphoma cell proliferation despite effective reduction of the H3K27me3 mark. We used MS1943, an EZH2 selective degrader, which successfully diminishes EZH2 levels in lymphoma cells. Additionally, lapatinib, a dual inhibitor of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) tyrosine kinases, targets a receptor protein that regulates cell growth and division. The overexpression of this protein is often observed in lymphoma cells. Our study aims to combine these two therapeutic targets to stimulate apoptosis pathways and potentially suppress Burkitt’s lymphoma cell survival and proliferation in a complementary and synergistic manner. We observed that a combination of MS1943 and lapatinib induced apoptosis in Daudi cells and caused cell cycle arrest at the S and G2/M phases in both Ramos and Daudi cells. This strategy, using a combination of MS1943 and lapatinib, presents a promising therapeutic approach for treating lymphoma and potentially Burkitt’s lymphoma. Full article
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Review

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38 pages, 1488 KiB  
Review
Lineage Plasticity and Stemness Phenotypes in Prostate Cancer: Harnessing the Power of Integrated “Omics” Approaches to Explore Measurable Metrics
by Souzana Logotheti, Eugenia Papadaki, Vasiliki Zolota, Christopher Logothetis, Aristidis G. Vrahatis, Rama Soundararajan and Vasiliki Tzelepi
Cancers 2023, 15(17), 4357; https://doi.org/10.3390/cancers15174357 - 1 Sep 2023
Cited by 1 | Viewed by 2113
Abstract
Prostate cancer (PCa), the most frequent and second most lethal cancer type in men in developed countries, is a highly heterogeneous disease. PCa heterogeneity, therapy resistance, stemness, and lethal progression have been attributed to lineage plasticity, which refers to the ability of neoplastic [...] Read more.
Prostate cancer (PCa), the most frequent and second most lethal cancer type in men in developed countries, is a highly heterogeneous disease. PCa heterogeneity, therapy resistance, stemness, and lethal progression have been attributed to lineage plasticity, which refers to the ability of neoplastic cells to undergo phenotypic changes under microenvironmental pressures by switching between developmental cell states. What remains to be elucidated is how to identify measurements of lineage plasticity, how to implement them to inform preclinical and clinical research, and, further, how to classify patients and inform therapeutic strategies in the clinic. Recent research has highlighted the crucial role of next-generation sequencing technologies in identifying potential biomarkers associated with lineage plasticity. Here, we review the genomic, transcriptomic, and epigenetic events that have been described in PCa and highlight those with significance for lineage plasticity. We further focus on their relevance in PCa research and their benefits in PCa patient classification. Finally, we explore ways in which bioinformatic analyses can be used to determine lineage plasticity based on large omics analyses and algorithms that can shed light on upstream and downstream events. Most importantly, an integrated multiomics approach may soon allow for the identification of a lineage plasticity signature, which would revolutionize the molecular classification of PCa patients. Full article
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Other

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17 pages, 651 KiB  
Perspective
Stem Cell Theory of Cancer: Clinical Implications for Cellular Metabolism and Anti-Cancer Metabolomics
by Shi-Ming Tu, Jim Z. Chen, Sunny R. Singh, Sanjay Maraboyina, Neriman Gokden, Ping-Ching Hsu and Timothy Langford
Cancers 2024, 16(3), 624; https://doi.org/10.3390/cancers16030624 - 31 Jan 2024
Cited by 1 | Viewed by 1596
Abstract
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 [...] Read more.
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. Full article
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18 pages, 575 KiB  
Perspective
Stem Cell Theory of Cancer: Clinical Implications of Epigenomic versus Genomic Biomarkers in Cancer Care
by Shi-Ming Tu, Jim Zhongning Chen, Sunny R. Singh, Ahmet Murat Aydin, Neriman Gokden, Neville Ngai Chung Tam, Yuet-Kin Leung, Timothy Langford and Shuk-Mei Ho
Cancers 2023, 15(23), 5533; https://doi.org/10.3390/cancers15235533 - 22 Nov 2023
Cited by 1 | Viewed by 1229
Abstract
Biomarkers play a crucial role in the diagnosis, prognosis, and therapeutics of cancer. We use biomarkers to identify, image, monitor, and target cancer. In many respects, the discovery of pertinent biomarkers that distinguish fulminant from indolent neoplasms and sensitive from refractory malignancies would [...] Read more.
Biomarkers play a crucial role in the diagnosis, prognosis, and therapeutics of cancer. We use biomarkers to identify, image, monitor, and target cancer. In many respects, the discovery of pertinent biomarkers that distinguish fulminant from indolent neoplasms and sensitive from refractory malignancies would be a holy grail of cancer research and therapy. We propose that a stem cell versus genetic theory of cancer may not only enable us to track and trace the biological evolution of cancer but also empower us to attenuate its clinical course and optimize the clinical outcome of patients with cancer. Hence, a biomarker that identifies cancer stem cells (CSCs) and distinguishes them from non-CSCs may serve to elucidate inter-tumoral and intra-tumoral heterogeneity, elevate the values and utility of current prognostic and predictive tests, and enhance drug versus therapy development in cancer care. From this perspective, we focus on CSC biomarkers and discuss stemness or stem-like biomarkers in the context of a unified theory and a consideration of stem cell versus genetic origin. We review their role in primary and mixed tumors, in the elaboration of tumor subtypes, and in the imaging and monitoring of minimal residual diseases. We investigate how scientific theories influence the direction of scientific research and interpretation of experimental results, and how genomics and epigenomics affect the dynamics and trajectories of biomarkers in the conduct of cancer research and in the practice of cancer care. Full article
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14 pages, 1172 KiB  
Perspective
Stem Cell Origin of Cancer: Implications of Oncogenesis Recapitulating Embryogenesis in Cancer Care
by Shi-Ming Tu, Ahmet Murat Aydin, Sanjay Maraboyina, Zhongning Chen, Sunny Singh, Neriman Gokden and Timothy Langford
Cancers 2023, 15(9), 2516; https://doi.org/10.3390/cancers15092516 - 27 Apr 2023
Cited by 4 | Viewed by 1892
Abstract
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 [...] Read more.
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? Full article
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