Mechanisms uncovered that turn oral stem cells cancerous

The molecular and cellular mechanisms that transform healthy stem cells into oral cancer at the earliest stages of the disease have been identified.

A research team at the University of California San Diego reported that a combination of two specific factors within oral stem cells could initiate tumour formation in mouse disease models. Publishing their findings in Nature Communications, the researchers were also able to track the origin of the cancer stem cells back to normal stem cells by monitoring changes in gene levels over time.

'We can understand precisely how you go from one cell state to another cell state and identify the very, very early events in tumour initiation rather than the final state of cancer,' said Professor J Silvio Gutkind, lead author and associate director at the University of California Moores Cancer Centre.

The study used state-of-art technologies to uncover the molecular mechanisms at a single cell level, including changes in gene, transcript, protein and metabolite levels and epigenetic modifications to understand better how oral cancer progresses over time.

Oral cancer belongs to a group of head and neck squamous cell carcinomas (HNSC), where tumours form in the upper airway epithelial cells, including the mouth, neck and throat. Around 30 percent of HNSC cases are attributed to the human papillomavirus (HPV). Within its genome, HPV has two oncogenes that, when activated, can cause cancer. When these oncogenes are activated in healthy cells, such as oral stem cells, they can degrade tumour-suppressing proteins and promote an uncontrolled increase in cell numbers.

In combination with the Yes-associated protein (YAP), which is also implicated in some cases of HSCS, HPV oncogenes were sufficient to initiate the transformation of healthy stem cells into cancer stem cells in mouse models of oral cancer. Additionally, immune cells were found to be reprogrammed to promote tumour invasion within the oral tissue.

The researchers now hope to identify how stem cells change in oral cancers of HPV-negative patients. For HPV-positive patients they aim to develop a drug that could block YAP function and potentially control aberrant cell division. Metformin, a drug originally developed for treating type 2 diabetes, is currently in Phase II clinical development to investigate whether it can prevent oral cancer, by interfering with YAP, in patients with precancerous oral conditions.