California [US]: A molecular mechanism important for the development of pancreatic cancers has been found by researchers at the University of California, San Diego School of Medicine. The mechanism could possibly contribute to the disease's great resistance to treatment and proclivity for metastasis.
The findings of the study published in Nature Cell Biology, found that pancreatic tumor-initiating cells must first overcome local 'isolation stress' by creating their own tumor-promoting microenvironment, and then recruit surrounding cells into this network. By targeting this tumor-initiating pathway, new therapeutics could limit the progression, relapse and spread of pancreatic cancer.
Pancreatic cancer is one of the most lethal cancers, notoriously resistant to treatment. Almost all patients experience cancer recurrence or metastasis. In the early stages of tumor formation, cancer cells (those with cancerous mutations, called oncogenes) experience a loss of adhesion to other cells and the extracellular matrix - the web of macromolecules that encase and support all cells. This isolation leads to a local lack of oxygen and nutrients. Most cells do not survive such isolation stress, but a certain group of cells can.
Tumor-initiating cells (TIC) play a major role in the formation, recurrence and metastatic spread of tumors. What sets them apart from other cancer cells is their resilience to these early substandard conditions. Like cacti in a desert, they can adapt to the harsh environment and set the scene for further tumor progression.
"Our goal was to understand what special properties these tumor-initiating cells have and whether we can control the growth and spread of cancer by disrupting them," said senior study author David Cheresh, PhD, Distinguished Professor and vice chair of the Department of Pathology at UC San Diego School of Medicine and a member of the UC San Diego Moores Cancer Center.
To answer these questions, first author Chengsheng Wu, PhD, a postdoctoral fellow in Cheresh's lab, subjected pancreatic cell lines to various forms of stress, including low oxygen and sugar levels. He then identified which cells could adapt to the harsh conditions and observed which genes and molecules were modified in these cells.
The stress-tolerant tumor-initiating cells showed reduced levels of a tumor-suppressive microRNA, miR-139-5p. This in turn led to the upregulation of Lysophosphatidic Acid Receptor 4 (LPAR4), a G-protein-coupled receptor on the cell surface. "LPAR4 is not normally found on happy cells, but it gets turned on in stressful environments to help the cells survive, which is particularly advantageous for tumor-initiating cells," said Cheresh. The researchers found that LPAR4 expression promoted the production of new extracellular matrix proteins, allowing the solitary cancer cells to start building their own tumor-supporting microenvironment.