Researchers in the U.S. and Taiwan have found that blocking a protein that is produced by normal stromal cells in the tumor microenvironment can hold back pancreatic cancer growth and metastasis in mice, and could represent a promising target for human drug development. “It looks like this protein might be a druggable target, so we're hoping that with some additional follow-up work, it's something that we'll see go into patients,” states Ellen Puré, Ph.D., chair of the department of biomedical sciences at the University of Pennsylvania School of Veterinary Medicine, who led the research. The Penn-Vet team and collaborators in Taiwan report their findings in Journal of Clinical Investigation Insight, in a paper entitled “Fibroblast Activation Protein Augments Progression and Metastasis of Pancreatic Ductal Adenocarcinoma.”
Scientists have previously found that the stromal tissue surrounding tumors can play a key role in either inhibiting or promoting tumor growth. Stromal tissue stiffness and density, for example, can impact both tumor growth and the ability of immune cells and drugs to reach the tumor. “If you take a tumor cell and put it on normal stroma, it will typically inhibit tumor growth,” Puré comments. “You need to have a permissive stroma to let a neoplastic cell grow out of control and eventually metastasize.”
Research reported by Dr. Puré’s team last year showed that inhibiting a stromal protein-cleaving enzyme, known as fibroblast activation protein (FAP), held back tumor growth in mouse models of lung and colon cancer. FAP acts to chop a key extracellular matrix component collagen into degradable fragments, and this FAP-dependent turnover of collagen effectively impacts on tumor growth. The mouse lung and colon cancer research indicated that inhibiting FAP led to an accumulation of extracellular matrix material, which blocked tumor growth because the undigested collagen prevented the tumor from receiving an adequate blood supply. “Collagen is something we have to understand a lot more about in the context of the tumor microenvironment,” Puré says. “A lot of people think it's just the amount of collagen present, but we're showing that it's more complicated; the architecture and structure play a critical role.”
In their latest studies Dr. Puré’s team investigated whether FAP could impact the growth of pancreatic tumors, cancer metastasis, and potentially pancreatic cancer survival. In humans, pancreatic cancer has a median survival time of just 6 months, and a five-year survival rate of less than 5%. The Penn-Vet-led team first looked at stromal FAP expression levels in 121 human clinical pancreatic tumor samples. They found that overexpression of FAP by stromal cells was predictive of poor overall and disease-free survival. “Univariate regression and multiple regression analyses of overall survival and disease-free survival indicated that FAP expression level was a significant, independent predictor of survival for patients with PDA [pancreatic ductal adenocarcinoma],” the authors write.
Turning to mouse models of pancreatic cancer, the team next found that knocking out FAP both held back the development of primary tumors and metastases, and also prolonged survival. Interestingly, their data indicated that FAP wasn’t necessary for tumor initiation, but it was required to accelerate the growth of pancreatic tumors, “and plays a critical role in promoting disease progression.” Moreover, while knocking out FAP didn’t affect tumor structure, FAP deficiency did result in increased necrotic tumor cell death, and this was associated with increased infiltration by lymphocytic cells, which indicates that FAP may normally act to block the immune system from controlling tumors. “…FAP expression may contribute to the resistance of PDAs to immune-mediated control of tumor progression,” they suggest. Further studies indicated that FAP enhances tumor metastasis and may drive tumor spread to other tissues. “Collectively, these data indicate that FAP protease expressed by stromal and/or tumor cells may play critical roles in the progression and metastasis of pancreatic cancer,” the authors conclude.
“We thought that by targeting this protein we would see a big change in the primary tumor, and, while we do see a delay, the big change was in the metastasis,” Puré notes. “This is the first time we've shown that FAP is important for promoting metastasis. By targeting FAP with a drug, we may be able to slow down the spread of the cancer by treating distal tissues that you don't even realize are getting ready to accept tumor cells, a phenomenon referred to as treating premetastatic niches. That is the hope.”
The researchers aim to further investigate how FAP promotes disease progression, and if its protein-cleaving role is found to be responsible, evaluate whether existing inhibitors might represent a starting point for human pancreatic cancer drug development.