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Stem Cell Theory of Cancer: Implications of a Viral Etiology in Certain Malignancies

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Stem Cell Theory of Cancer: Implications of a Viral Etiology in Certain Malignancies cancers Viewpoint Stem Cell Theory of Cancer: Implications of a Viral Etiology in Certain Malignancies Shi-Ming Tu Department of Genitourinary Medical Oncology, Unit 1374, The University of Texas, MD Anderson Cancer Center, 1155 Pressler Street, Houston, TX 77030-3721, USA; [email protected]; Tel.: +1-(713)-563-7268; Fax: +1-(713)-745-1625 Simple Summary: We postulate that a virus is more likely to cause cancer when it infects a progenitor stem-like cell rather than a progeny differentiated cell. We propose that the virus may turn out to be a surreptitious agent and a serendipitous model in our quest to investigate the origin of cancer. When it pertains, oncology recapitulates ontogeny, although genetic makeup is king. Cellular context may be the key to elucidating a stem cell origin of cancer. Abstract: In 1911, Peyton Rous (Nobel Prize winner in 1966) demonstrated that a virus (i.e., RSV) caused cancer in chickens. In 1976, Bishop and Varmus (Nobel Prize winners in 1989) showed that the cellular origin of retroviral oncogenes was actually normal cellular genes (i.e., proto-oncogenes). In this article, we revisit the role viruses play in the genetic origin of cancer. We review a link between viruses or cancer and autoimmunity in an alternative stem cell origin of cancer. We propose that a virus is more likely to cause cancer when it infects a progenitor stem-like cell rather than a progeny differentiated cell. We postulate that both known (e.g., HBV and HPV) and novel viruses (e.g., SARS-CoV-2) pose an imminent threat in the emergence of chronic viral diseases as well as virally induced malignancies. Knowing the origin of cancer has profound implications on our current conception and perception of cancer. It affects our conduct in cancer research and our delivery of cancer care. It would be ironic if viruses turn out to be a useful tool and an ideal means in our quest to verify a genetic versus stem cell origin of cancer. When it pertains, oncology recapitulates ontogeny; Citation: Tu, S.-M. Stem Cell Theory although genetic makeup is pivotal, cellular context may be paramount to elucidating a stem cell of Cancer: Implications of a Viral origin of cancer. Etiology in Certain Malignancies. Cancers 2021, 13, 2738. https://doi.org/ Keywords: cancer stem cell; COVID-19; HBV; HPV; SARS-CoV-2; autoimmunity 10.3390/cancers13112738 Received: 9 April 2021 Accepted: 26 May 2021 “Gentlemen, it is the microbes who will have the last word.” Published: 1 June 2021 (Messieurs, c’est les microbes qui auront le dernier mot) Louis Pasteur Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in At present, many people are worried about a novel virus, SARS-CoV-2, and afraid of published maps and institutional affil- the strange disease, COVID-19. We are anxious about the economics of the pandemic. We iations. are nervous about our welfare and healthcare. We are curious about what makes this virus so treacherous and dangerous. It is true that viruses are part of life. They are ubiquitous and multitudinous. Most viruses are innocuous. Some are pathogenic. A few may be malignant. Many of us may not realize that viruses may also cause cancer [1]. Viral infection is Copyright: © 2021 by the author. Licensee MDPI, Basel, Switzerland. associated with cancer formation. We find viral DNA embedded (integrated or episomal) This article is an open access article within the cancer genome [2]. However, it is evident that most viruses do not cause cancer. distributed under the terms and We also detect viral DNA in non-cancer cells [3]. conditions of the Creative Commons Importantly, what makes a virus oncogenic may allude to the very origin of cancer. Attribution (CC BY) license (https:// Knowing the origin of cancer would have profound implications on our current creativecommons.org/licenses/by/ conception and perception of cancer. It would affect our conduct in cancer research and 4.0/). our delivery of cancer care. Cancers 2021, 13, 2738. https://doi.org/10.3390/cancers13112738 https://www.mdpi.com/journal/cancers Cancers 2021, 13, x 2 of 10 Cancers 2021, 13, 2738 Knowing the origin of cancer would have profound implications on our2 of current 10 con- ception and perception of cancer. It would affect our conduct in cancer research and our delivery of cancer care. We postulate that a virus is more likely to cause cancer when it infects a progenitor We postulatestem-like that cell a virus rather is morethan a likely progeny to cause differe cancerntiated when cell (Figure it infects 1). a We progenitor propose that the stem-like cellvirus rather may than turn a progeny out to be differentiated a useful tool and cell (Figurean ideal1 ).means We propose in our quest that theto verify virus the origin may turn outof to cancer. be a useful When toolit pertains, and an oncology ideal means recapi intulates our quest ontology; to verify viral the content origin may of be king, cancer. Whenbut it pertains,cellular context oncology is key. recapitulates ontology; viral content may be king, but cellular context is key. Figure 1. VirusesFigure and 1. cancer.Viruses A and virus cancer. is more A likely virus to is cause more malignant likely to cause tumors, malignant chronic infections, tumors, chronic and autoimmune infections, com- plications whenand it autoimmune infects a progenitor complications cell with when stem-like it infects properties a progenitor rather than cell a with progeny stem-like cell with properties mature phenotypes rather (illustrated bythan Benjamin a progeny Tu). cell with mature phenotypes (illustrated by Benjamin Tu). 1. A Brief History1. A Brief History People may forgetPeople thatmay the forget discovery that the of discovery viral oncogenes of viral oncogenes laid the groundwork laid the groundwork for a for a genetic theorygenetic of cancer. theory In of 1911, cancer. Rous In demonstrated1911, Rous demonstrated that a virus that (named a virus Rous (named sarcoma Rous sarcoma virus or RSV)virus caused or RSV) cancer caused in chickens cancer in [4 ].chickens By creating [4]. By mutant creating viruses mutant that viruses no longer that no longer caused tumors,caused Duesberg tumors, and Duesberg Vogt managed and Vogt to managed attribute RSV’sto attribute cancer-causing RSV’s cancer-causing ability to a ability to single gene (i.e.,a single an oncogene, gene (i.e., knownan oncogene, as SRC) known in the as virus SRC) [5 in]. Inthe 1976, virus Bishop [5]. In 1976, and Varmus Bishop and Var- showed that themus cellular showed origin that the of retroviralcellular or oncogenesigin of retroviral was actually oncogenes normal was actually cellular normal genes cellular (i.e., known asgenes proto-oncogenes) (i.e., known as [ 6proto-oncogenes)]. In 1989, Bishop [6]. and In Varmus 1989, Bishop received and theVarmus Nobel received Prize in the Nobel Physiology orPrize Medicine in Physiology “for their or discovery Medicine of “for the their cellular discovery origin ofof retroviralthe cellular oncogenes. origin of ”retroviral Unbeknownstoncogenes.” to most people, Dolberg and Bissell performed a perplexing experiment with provocative resultsUnbeknownst [7]. When to most they people, injected Dolberg RSV into and 4-day-old Bissell performed chicken embryos, a perplexing no experi- tumors formed,ment even with though provocative there was results v-Src [7]. activation When they and widespreadinjected RSV RSV into infection 4-day-old in thechicken em- bryos, no tumors formed, even though there was v-Src activation and widespread RSV embryo. In contrast, the same virus was tumorigenic in newly hatched chicks. Furthermore, infection in the embryo. In contrast, the same virus was tumorigenic in newly hatched the infected embryonic cells did form tumors when grown outside the embryo. It seems chicks. Furthermore, the infected embryonic cells did form tumors when grown outside that the embryonic niche harbored a mysterious force and harnessed a magical power that protected cells from cancer formation. Somehow, it managed to block tumorigenesis despite the expression of oncogenic v-Src. 2. Virally Induced Malignancies Undoubtedly, Nature has already performed and is still performing some of the most astounding experiments to inform us about the origin and nature of cancer. In fact, Nature Cancers 2021, 13, 2738 3 of 10 is providing us tantalizing proof through various viral infections that cancer is a stem cell disease and has a stem cell origin. When stem cells are chronically irritated and irreparably damaged, malignancy almost invariably ensues. This happens in the lungs of a heavy smoker, in the colon of somebody with ulcerative colitis, and in the liver of a person with chronic hepatitis. However, when only differentiated progeny cells are affected and the progenitor stem cells remain intact, the latter is poised to repair any badly wounded tissues and regenerate any collaterally damaged organs. Therefore, the regulation of viral lytic and latent cycles in a progeny cell or a progenitor cell may be key for viral-induced tumorigenesis [8]. Viral lytic replication is more likely to occur in an active differentiated cell than a quiescent stem-like cell. An episomal viral genome is less likely to be lasting in a transient progeny cell than a permanent progenitor cell. We propose that both persistent infection-clonal expansion and hit-and-run carcinogenesis are less plausible in a progeny cell compared with a progenitor cell. Hence, hepatitis B virus (HBV) harms liver progenitor cells and elicits hepatocellular carcinoma (HCC) [9,10]. HPV disturbs progenitor cells in the epidermal tissues and causes squamous cell carcinoma in the cervix and penis [11]. Epstein–Barr virus (EBV) disrupts progenitor cells in the head and neck and causes nasopharyngeal carcinoma (NPC) [12]. 3. Stem Cell Origin of Cancer When viruses infiltrate differentiated progeny cells, our immune cells recognize the virally infected cells and contain the viral infection.
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