Healthy cells shown to promote tumor growth

Researchers at the Institute of Cancer Research, London and the Cancer Research UK Manchester Institute of the University of Manchester recently published a paper in Cell. It implicated one of the most common mutated genes across all cancers, KRAS, in the acceleration of tumor growth. KRAS shows up in more than 90 percent of pancreatic cancers.

This hyperactive mutant version of the gene contributes to the uncontrollable growth typical of cancer cells. The novel finding is that the version of this gene found in normal, healthy cells responds to the presence of the cancer cell signals and further drives malignancy.

Many might think of tumors as dense clusters of abnormal cells, but the truth is that some types of tumors can have large proportions of healthy cells in the mix.

The discovery of the healthy KRAS gene’s “bullied” contribution to cancer development shows that these healthy cells, while not cancerous themselves, may be contributing to the number of bad cells. This is the first time a cancer-causing gene is implicated in a communication cycle between malignant and healthy cells.

As the authors note in the abstract, this new “reciprocal signaling axis” allows for a whole new set of proteins to be modified, distinct from the proteins expected from traditional models of tumor growth. These new distinctions not only change the paradigm of tumorigenesis, but also provide new targets for drug development.

The researchers, under Claus Jorgensen of Systems Oncology of the Manchester Institute, analyzed the effects of thousands of protein factors on a different cells of a specific tumor subtype, pancreatic ductal adenocarcinoma (PDA). PDA is one of the deadliest forms of pancreatic cancer, and KRAS is known to be predominantly mutated in this type of cancer.

To study the effects of the KRAS gene in both cancerous and healthy cells, these scientists analyzed their different “phosphoproteomes,” a term that refers to all the proteins in a cell which have a phosphate chemical group attached to it. This molecular phoshpate tag gives the cell a sense of which proteins or pathways are “activated” at any given time.

According to Joregensen, by looking at which pathways are activated in tumor cells affected by mutant KRAS, versus those “reciprocally regulated” by healthy cells in the tumor, different types of molecules and pathways have been found to be involved.

Between the two, the tumor cells exhibited different growth properties, such as increased energy performance, greater proliferation and resistance to cell death for these “reciprocally” affected types.

This means the traits of tumors in the presence of these healthy fibroblast cells can be radically transformed. The researchers note that this could be an important consideration to keep in mind for pharmaceutical research. The idea that tumors are more than just a single cell type gone wrong, but a minor ecosystem of interacting cells, may be extremely important for future cancer therapies in the years ahead.

Jorgenson elaborated on the significance of the discovery.

“We now know that tumours are a complex mix of genetically diverse cancer cells and multiple types of healthy cells, all communicating with each other via an intricate web of interactions,” Jorgenson said, according to Nature Journal. “Untangling this web, and decoding individual signals, is vital to identify which of the multitude of communications are most important for controlling tumour growth and spread. We have identified a key role played by the most commonly mutated gene in cancer in communicating with healthy cells. Blocking its effects could be an effective cancer treatment.”