With nearly 60,000 people being diagnosed with oral cancer (cancer in the oral cavity or oropharyngeal region) in the U.S. every year, and more than 375,000 cases globally, the disease is a significant health concern and remains, according to the American Cancer Society (ACS), the sixth most common cancer worldwide with the rate of new cases continuing to rise.[1]. The incidence and mortality vary by geographic area and demographics, with men more often diagnosed than women (male-to-female ratio 2:1).[2]
Oral cancer — also known as head and neck squamous cell carcinoma (HNSC) — is a group of malignancies that affects the mouth, throat, nose, sinuses, and voice box. The cancer takes root in epithelial cells, the top layer of cells lining these cavities. Around 30% of oral cancer cases are caused by human papillomavirus (HPV). [3]
Affecting the upper aerodigestive epithelia, the leading risk factors generally linked to the development of neck squamous cell carcinoma include alcohol consumption and tobacco use (according to studies, 75% of cases in Western Europe are linked to tobacco* | **).[4][5] However, oral cancer can affect people of all ages and is not necessarily limited to people who smoke or consume alcohol. Other risk factors include human papillomavirus (HPV) infection (particularly HPV 16; oropharyngeal cancers), and Epstein–Barr virus (EBV) infection (nasopharyngeal cancers).[4][5][6]
Diagnosing oral cancer
Among healthcare professionals playing a critical role in detecting oral cancer early, are dental hygienists and dentists. They commonly offer oral cancer screenings as part of their routine screening exam, using a combination of oral cancer screening methods, including a visual exam, palpation, and oral screening dyes and lights. However, they don’t diagnose. When they find signs of cancer or find anything suspicious, they’ll refer their patients to an oncologist for further testing, diagnosis, and treatment.
Building on the documented details from either dental hygienists or dentists can lead to early diagnosis, successful treatment, and a better health-related Quality of Life (hrQoL).
How does HNSC develop
Oral cancers,*** like other forms of cancer, develop over many years. During this period, neoplastic transformation, a highly complex multistep and multifocal process involving genetic and epigenetic changes by which normal or ‘healthy’ cells acquire the characteristics of cancer, promotes uncontrolled cell growth. This process takes place when several genetic alterations are the affecting squamous epithelium.
Exposure to carcinogens such as tobacco or alcohol (or both) damages DNA in the epithelial cells of the head and neck, causing mutations that initiate the development of oral cancer. Over time, these mutated cells, as a result of altered cellular signaling pathways, begin to proliferate, leading to precancerous lesions, and ultimately promoting the development of cancer. [7]
People who use chewing or smokeless tobacco are especially at risk for squamous cell carcinoma, considered the second most common form of skin cancer, because squamous cells make up the mucosa layer (which is the outermost lining) of tissue on the inside of the mouth, including the lips and cheeks. As a result, chewing tobacco brings the skin’s squamous cells in direct contact with the tobacco and the various carcinogenic additives. This, in turn, may lead to something that seems harmless, little white or red bumps inside the month. However, if these lesions or sores do not go away within a few days, further evaluation is needed.
Another cancer-associated risk includes a pre-cancerous condition called oral submucous fibrosis, which causes the tissue in the jaw to become stiff, limiting the patients from fully opening their mouths.
Finding leading to improvement
Diving deeper into the development of oral cancer, researchers at the University of California San Diego have discovered how healthy stem cells are transformed into cancer stem cells in the (very) earliest stages of the disease.
Researchers have conducted extensive molecular characterization of HNSC has revealed that alterations in numerous genes in a given tumor converge to impact a finite set of oncogenic molecular pathways.
The results of their study were published on January 8, 205 in Nature Communications.[8]
YAP-activation
By activating a signaling protein called YAP (yes-associated protein, a transcription factor normally involved in stem cell maintenance and growth promotion) in combination with HPV oncogenes (genes that inhibit the normal suppression of tumor growth), the researchers triggered a cascade of cellular and molecular changes that reprogrammed normal stem cells into cancer cells in a mouse model.
The researchers used several state-of-the-art technologies to trace the progression of changes that transformed healthy stem cells into cancer stem cells at the resolution of the single cell.
The study is the first to use technologies such as cell tracing (marking cells to follow their proliferation through time) and multi-omics (analyzing molecular data from genomics, RNA transcription, protein expression, epigenetic changes, and cellular metabolites to understand disease development) at the resolution of single cells to follow the real-time progression of these changes in a living organism.
“We can understand precisely how you go from one cell state to another cell state and identify the very, very early events in tumor initiation rather than the final state of cancer,” noted senior author J. Silvio Gutkind, Ph.D., Distinguished Professor and chair at UC San Diego School of Medicine Department of Pharmacology, and associate director for basic science at UC San Diego Moores Cancer Center.
The researchers found that activating YAP in combination with HPV oncogenes:
- Resulted in invasive cancer within just 10 days;
- Caused a loss of normal cell identity by halting normal cell differentiation, leading to the acquisition of a more mobile and invasive state;
- Promoted unrestrained cell proliferation by promoting epigenetic changes and stimulating pathways related to carcinoma cell growth, survival, and migration; and
- This resulted in the secretion of factors that recruited and reprogrammed immune cells to break down tissue barriers, evade immune detection, and facilitate tumor cell invasion.
Potential New Treatment Options
Gutkind says the next step is to use the same technologies to understand what leads to the progression of normal stem cells to cancer stem cells in HPV-negative oral cancers, which are most common in smokers and older patients. His team is also exploring whether recently developed drugs that block YAP function may provide new treatment options for oral cancers.
He adds that the research paves the way for the development of therapeutics to target HPV-positive cancers at their very earliest stages. He notes that an existing drug, metformin, an inexpensive medication that has long been used to control blood sugar in diabetic patients, is one promising candidate.
A clinical trial is currently underway at UC San Diego to test whether metformin interferes with YAP, for example, in patients with oral pre-malignancies.
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Note: * A case-control study carried out in the city of Turin and the province of Varese (Italy), the provinces of Navarra and Zaragoza (Spain), the canton of Geneva (Switzerland), and the département of Calvados (France), included 1,147 male cases and 3,057 male population controls.[4]
** The use of tobacco. including smoking cigarettes, cigars, pipes, and smokeless tobacco, but also chewing tobacco, which contains many cancer-causing chemicals, including tobacco-specific nitrosamines (TSNAs). These chemicals are known to mutate the cells in the mouth and throat, which can lead to cancer. In addition, chewing tobacco contains nicotine, which is highly addictive.
*** Oral cavity and larynx cancers are generally associated with tobacco consumption, alcohol abuse or both, whereas pharynx cancers are increasingly attributed to infection with human papillomavirus (HPV), primarily HPV-16.
Reference
[1] Tranby EP, Heaton LJ, Tomar SL, Kelly AL, Fager GL, Backley M, Frantsve-Hawley J. Oral Cancer Prevalence, Mortality, and Costs in Medicaid and Commercial Insurance Claims Data. Cancer Epidemiol Biomarkers Prev. 2022 Sep 2;31(9):1849-1857. doi: 10.1158/1055-9965.EPI-22-0114. PMID: 35732291; PMCID: PMC9437560.
[2] Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021 May;71(3):209-249. doi: 10.3322/caac.21660. Epub 2021 Feb 4. PMID: 33538338.
[3] Barsouk A, Aluru JS, Rawla P, Saginala K, Barsouk A. Epidemiology, Risk Factors, and Prevention of Head and Neck Squamous Cell Carcinoma. Med Sci (Basel). 2023 Jun 13;11(2):42. doi: 10.3390/medsci11020042. PMID: 37367741; PMCID: PMC10304137.
[4] Tuyns AJ, Estève J, Raymond L, Berrino F, Benhamou E, Blanchet F, Boffetta P, Crosignani P, del Moral A, Lehmann W, et al. Cancer of the larynx/hypopharynx, tobacco, and alcohol: IARC international case-control study in Turin and Varese (Italy), Zaragoza and Navarra (Spain), Geneva (Switzerland) and Calvados (France). Int J Cancer. 1988 Apr 15;41(4):483-91. doi: 10.1002/ijc.2910410403. PMID: 3356483.
[5] Conway DI, Purkayastha M, Chestnutt IG. The changing epidemiology of oral cancer: definitions, trends, and risk factors. Br Dent J. 2018 Nov 9;225(9):867-873. doi: 10.1038/sj.bdj.2018.922. PMID: 30412558.
[6] Oral Cancer Facts. (n.d.). Oral Cancer Foundation. Online. Last accessed on February 4, 2025.
[7] Tanaka T, Ishigamori R. Understanding carcinogenesis for fighting oral cancer. J Oncol. 2011;2011:603740. doi: 10.1155/2011/603740. Epub 2011 May 12. PMID: 21772845; PMCID: PMC3136173.
[8] Faraji F, Ramirez SI, Clubb LM, Sato K, Burghi V, Hoang TS, Officer A, Anguiano Quiroz PY, Galloway WMG, Mikulski Z, Medetgul-Ernar K, Marangoni P, Jones KB, Cao Y, Molinolo AA, Kim K, Sakaguchi K, Califano JA 3rd, Smith Q, Goren A, Klein OD, Tamayo P, Gutkind JS. YAP-driven malignant reprogramming of oral epithelial stem cells at single-cell resolution. Nat Commun. 2025 Jan 8;16(1):498. doi: 10.1038/s41467-024-55660-6. PMID: 39779672; PMCID: PMC11711616.
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