Tobacco use causes precancerous cells to "fertilize" neighboring cells with cancerous changes

Tobacco creates a field of precancerous cells, increasing the risk of cancer of the head and neck. But we have often neglected to know how this precancerous field influences cancer. A study from the University of Colorado Cancer Center presented at the annual conference of the American Association for Cancer Research (AACR) in 2019 offers an interesting idea: maybe these precancerous cells "fertilize" the cells with cancerous changes to develop and resist treatment.

"We wanted to understand how these precancerous cells can impact neighboring cancer," said Christian Young, PhD, research fellow at the UC Cancer Center and lead author of the study. The present study explores this communication between precancerous and cancerous cells in the context of an enzyme called PI3K.

The PI3K enzyme is activated in many cancers, even in most cancers, and some researchers believe that overactivation of PI3K is an essential feature of the disease. Interestingly, PI3K is a "kinase" and the clbad of drugs known as kinase inhibitors has been shown to be effective against many types of cancers, eg erlotinib against EGFR + and crizotinib against ALK cancers +. Kinase inhibitors have also been developed against PI3K and, on the whole, they are very good at killing cancer cells in dishes. The question is why PI3K inhibitors do not necessarily work in patients – what do cancer cells do to resist this therapy that should kill them?

The current study offers an intriguing clue: "These cancer cell lines in culture are sensitive to PI3K inhibition, but when you put them next to precancerous cells, they become resistant," says Young.

To explore this observation, Young and his colleagues, including first author Khoa Nguyen, an undergraduate student at CU Boulder University, developed cancer cells of the head and neck in the same dish as precancerous cells (called NOK cells), then hit cells, alone and together, with PI3K inhibitors. Cancer cells cultured with NOK cells grew faster and resisted the inhibition of PI3K compared to cancer cells grown alone. When the researchers cultivated NOK cells alone, then removed them and the cancer cells "fertilized" with the culture medium in which the NOK cells were developed, they found similar growth of the cancer cells and a resistance to PI3K inhibitors.

In addition, NOK cells stimulated cells resembling cancer stem cells in recipient cancer cells. This means that in addition to resistance to PI3K treatment, cancer cells that coexist with precancerous cells can themselves become more dangerous, for example, more likely to restart the disease.

"This means that some of the properties of cancer cells may not necessarily be intrinsic, and in our study, cancer cells have been badigned some of their cancer and stem cell-like properties by nearby precancerous cells," says Young.

Continuing the study, Young and his team asked what these precancerous cells gave to cervical and cervical cancer cells, which allowed them to resist PI3K treatment and to obtain traits similar to those of cancer stem cells. . Using the SomaScan proteomics platform of the Cancer Center of Cancer Center's Microarray shared resource, the team was able to badyze more than 1,300 proteins found in boxes in which NOK cells been cultivated. What they found, it is a dramatic increase in the number of EGFR ligands. Do you think that PI3K is a driver of cancer growth. EGFR is another engine that can work alongside PI3K. In this badogy, EGFR ligands are like a fuel, allowing cancer cells, in the absence of PI3K, to fuel their growth and survival through the EGFR engine. .

"It's the precancerous cells that provided that fuel," says Young.

Ongoing work is shifting Young's basic science to mouse models of head and neck cancer. Ultimately, the goal could be to inhibit the EGFR at the same time as PI3K, possibly reversing the EGFR output pathway that precancerous cells seem to provide to cancerous cells. .