Several highly esteemed Institutes such as the Mayo Clinic and CONICET have identified critical elements contributing to the aggressiveness of Pancreatic cancer. The survival rate at the five-year mark is one of the lowest, at about ten percent. As reported by News Medical Life Sciences, details are provided in the journal PNAS which sets out new insights into the cells’ roles in pancreatic cancer’s progression.
RAS Inhibitors:
Recent studies involving KRAS inhibitors have led to more effective therapies. However, the rapid appearance of tumors continues to limit any beneficial effect because of tumor resistance.
Stroma vs Stromal Cells:
Stroma itself is not considered to be a tumor. Stroma supports an organ’s connective tissue. On the other hand, a stromal tumor is a form of cancer arising within the tissue.
Although stroma is normal tissue it may become part of the tumor microenvironment by supporting the growth of cancer activated stroma cells produce cytokines, growth factors and a stiffened matrix driving the survival of tumor cells and invasion.
Galectin-1:
A recent study led to discovery of the protein Galectin-1. It is in the nuclei of fibroblasts that form cellular tissue producing collagen and other fibers. Therefore Galectin-1 is a glycan-binding protein versus stroma which is the non-cancerous tissue that supports tumors and organs.
Dr. Pilar Navarro, coordinator of the Cancer Molecular Research Group Hospital Del Mar, explains that stromal cells, with emphasis on fibroblasts, produce substances that promote tumor growth and dispersal. Contrary to what has been observed thus far, fibroblasts were known to be secreting Galectin-1 which is a protein that has pro-tumoral properties.
According to Dr. Navarro, a new study indicates that the molecule is also located inside the nuclei of fibroblasts which allows it to be a major player of gene expression regulation.
KRAS is one of the genes it regulates. It plays a critical role in pancreatic tumors, according to Dr. Navarro. The gene is also found in tumor cells in ninety percent of patients. In this case, however, KRAS is mutated. It is considered to be one of the prominent drivers of uncontrolled growth and tumor aggressiveness.
Its presence activates fibroblasts facilitating support of the development of tumor cells. The research team discovered that Galectin-1 regulates gene expression in the cells without alteration of the DNA sequence through epigenetic control.
According to Dr. Navarro, Galectin-1 regulates KRAS which plays a critical role in pancreatic tumors. It has a presence in ninety percent of patients. However, in this case KRAS is mutated. It is recognized as one of the primary drivers of uncontrolled growth and tumor aggressiveness.
Until recently, fibroblasts were recognized as secreting Galectin-1 which is a protein having pro-tumoral properties. This new study now demonstrates that Galectin-1 is located inside the nuclei of fibroblasts thereby playing a major role in regulating gene expression. In addition, the research team found that Galectin-1 regulates gene expression in cells at a specific level without affecting the DNA sequence.
Dr. Navarro commented further specifically mentioning that Galectin-1 regulates the KRAS gene. It plays a critical role in pancreatic tumors. Galectin-1 is one of the foremost drivers of tumor aggressiveness and uncontrolled growth.
Designing New Strategies
The aforementioned newly identified functions pave the way to develop new strategies. The focus to date has been to inhibit Galectin-1 when it is secreted by the stoma around the tumor.
Dr. Neus Bosch at the Hospital del Mar Research Institute confirmed that the protein inside the nuclei must be blocked in addition to the protein inside the fibroblast nuclei.
The challenge will be the identification of new inhibitors inside the fibroblasts and also protein as it is secreted. Tissue samples obtained from pancreatic cancer patients were used by the researchers allowing the team to study Galectin-1 found in fibroblast nuclei. In addition, the team performed vitro experiments using human fibroblast cell lines to investigate effects of inhibiting the protein and the KRAS gene. The team observed deactivation of the cells thus ending cooperation with tumor cells.
Dr. Judith Vinaixa, first author of the study and researcher at Hospital del Mar emphasized the importance of the study results. The doctor stated that the key role of Galectin-1 in the cell nucleus has been established where it regulates expression of multiple genes that are critical for the behavior of cells.
Researcher Gabriel Rabinovich Ph.D. at CONICET and Caixa R.I. added that the next challenge will be to explore therapeutic combinations inhibiting extracellular as well as intracellular Galectin-1 which participates in critical processes such as the formation of blood vessels and causing resistance to immunotherapy. The strategy is especially relevant considering the multitude of antitumoral effects of Galectin-1 inhibition.
