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



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The use of tobacco causes a pre-cancerous cell field, increasing the risk of developing head and neck cancer. But exactly how this precancerous field influences cancer has often been overlooked. Now, a study from the University of Colorado Cancer Center presented at the American Cancer Research Association's (AACR) Annual Meeting in 2019 offers an interesting idea: perhaps these precancerous cells "fertilize" nearby cells with cancerous changes to grow and resist cancer. therapy.

"We wanted to understand how these precancerous cells can affect the neighboring cancer," says Christian Young, PhD, research instructor at CU Cancer Center and senior 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 or even most cancers, with some researchers considering the excessive activation of PI3K an essential feature that drives the disease. Atractively, PI3K is a "kinase" and the class of drugs known as kinase inhibitors has been shown to be effective against a number of cancers, for example erlotinib against EGFR + cancers and crizotinib against ALK + cancers. Kinase inhibitors have also been developed against PI3K and generally do a great job of killing the cancer cells on the dishes. The ongoing question has been why PI3K inhibitors do not necessarily work in patients – what are the cancer cells doing to resist that therapy that should kill them?

The current study offers an intriguing tip: "These cancer cell lines in culture are sensitive to inhibition of PI3K, 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, a graduate student at CU Boulder, developed head and neck cancer cells in the same dish as precancerous cells (called NOK cells) and then cells, alone and together. with PI3K inhibitors. Cancer cells grown with NOK cells grew faster and resisted inhibition of PI3K compared to cultured cancer cells alone. When the researchers cultured only NOK cells, they removed the cells and "fertilized" the cancer cells with the culture medium in which NOK cells grew, observed similar growth of cancer cells and resistance to PI3K inhibitors.

In addition, NOK cells were stimulating cancer-like characteristics in cancerous recipient cells. This means that in addition to resisting PI3K therapy, cancer cells that are next to precancerous cells can become more dangerous, for example, more capable of restarting the disease.

"What this means is that some properties of cancer cells may not necessarily be intrinsic. In our study, cancer cells received some of their cancer-like and stem-like properties by nearby precancerous cells," says Young.

Continuing the line of study, Young and his team asked what these precancerous cells gave to the head and neck cancer cells that allowed them to resist PI3K therapy and gain traces similar to cancer stem cells. Using the SomaScan proteomic platform at the CU Cancer Center's Microarray Shared Resource, the team was able to analyze more than 1,300 proteins found on dishes in which NOK cells were cultured. What they have discovered is a dramatic increase in EGFR ligands – think of PI3K as a motor that drives cancer growth. EGFR is another mechanism that can work together with PI3K. In this analogy, EGFR ligands are as fuel, allowing cancer cells, in the absence of PI3K, to boost their growth and survival through the EGFR mechanism.

"It was the precancerous cells that were supplying this fuel," says Young.

Continuing work is taking Young's basic science to models of rats with head and neck cancer. Eventually the goal may be to inhibit EGFR together with PI3K, perhaps by negating the escape route of EGFR that precancerous cells appear to be delivering to cancer cells.

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