According to Weill Cornell Medicine, tumors may entail growth by releasing lactate into their local environment. They set the stage for future treatment that would alter that defense mechanism to assist cancer patients.
The researchers explored how tumors, as they develop, use nearby cell called fibroblasts to function as their enablers. Fibroblasts are normally connected to the stroma, or connective tissue of organs, and have often been beneficial repair and maintenance functions. However, cancer-associated fibroblasts (CAFs) obtain properties that enable them to assist tumors in ways that make the tumors more malignant and difficult to digest.
Researchers discovered that PARP-1 inhibitors, a widely used cancer medication, simply mimic the majority of CAF recruiting procedures, and thus may increase their effectiveness by transforming local fibroblasts to this cancer-enabling mode.
Future therapy that prevent this cancer-associated state of fibroblasts might be beneficial on their own or as a way to improve the effectiveness of PARP-1 inhibitors, according to a co-senior author Dr. Maria Diaz-Meco, the Homer T. Hirst III Professor of Oncology in Pathology and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine.
Dr. Diaz-Meco collaborated in a research with Dr. Jorge Moscat, a co-senior author, and a member of the Homer T. Hirst III Professor of Oncology in Pathology and a member of the Meyer Cancer Center at Weill Cornell Medicine. The co-first authors are Dr. Juan Linares, an instructor in pathology and laboratory medicine, and Dr. Tania Cid-Diaz, a postdoctoral associate in pathology and
Development tumors are often used to improve their local environment in ways that ensure their own survival and development. Cancer-associated fibroblasts are a key component of the tumor microenvironment in the prostate, lung, colon, and other cancer types. These individuals are therefore considered as a promising complementary approach to standard cancer therapy. This means that they may well work against cancers of different cellular and genetic origins.
Cancer-associated fibroblasts stimulate tumor growth by introducing growth factors and essential metabolites to the tumor, by fending-off anti-tumor immune cells, and in many other ways. The result is a tumor that is more malignant and treatment-resistant.
The Moscat and Diaz-Meco laboratories discovered a protein called p62, which is applied to fibroblasts, suppresses the CAF state several years ago, although many tumors believe that reducing production of p62 would help restore this state. In a new study, they showed that tumors achieve this by secreting high levels of an organic substance called lactate, also known as lactic acid.
Lactate is a standard byproduct of certain energy-production processes in tumors that are often hyperactive. In experiments with prostate cancer cells, researchers investigated the molecular chain of events by which tumor-secreted lactate disrupted the normal metabolism of fibroblasts, resulting in a decrease in p62 gene activity and the activation of the tumor-enabling CAF state.
The conclusion on its own is significant because it illuminates a major cancer-promoting process, which in principle may be associated with future therapies as a standalone or add-on treatment strategy.
Another, surprising discovery was the inhibition of a DNA-repair enzyme called PARP1. There were a few studies demonstrating that these drugs may be working partly against themselves by creating a more tumor-friendly microenvironment.
The researchers discovered in cancer cells and mouse models that the PARP1 inhibitor olaparib reduces p62 in fibroblasts and pushes them into the CAF state, which in turn increases tumor resistance to the drugs'' primary cancer-killing effects.
Future therapies that reprogram CAF cells to the non-cancer state or prevent their development might greatly improve PARP1 inhibitors anti-tumor effectiveness, according to the researchers.
Dr. Moscat said he is currently researching several potential CAF-blocking therapies in our clinics.
Many Weill Cornell Medicine physicians and scientists maintain close communication, provide expert guidance, and foster scientific innovation. The institution makes these disclosurespublic, which is designed to ensure transparency. For this information, see Dr. Maria Diaz-MecoandDr. Jorge Moscat.