In most pancreatic cancer patients, the diagnosis is made when the disease is already advanced, and there is no effective treatment at present. There have been no significant advances to combat it in recent decades and unfortunately, its occurrence is on the increase.
‘In pancreatic cancer, elimination of Saa3 gene expression in the cancer associated fibroblasts (CAFs) can make the tumor cells behave like normal fibroblasts losing their ability to progress.’
"This tumor is so aggressive and so complex that it is necessary to try and attack it from various sources, not only tumor cells. Our work opens the door to the design of future therapeutic strategies. However, it is still too early to think about its clinical use," according to the research team.
One of the characteristics of pancreatic cancer is that the tumor cells are embedded in the stroma, which represents 90% of the tumor mass and which seems to form a barrier (physical and chemical) hindering treatment with inhibitors, chemotherapy and immunotherapy. Most of the studies have focused mainly on tumor cells, whilst the cells that form the stroma are the great unknown, in spite of different research groups proving that some components of stroma promote the tumor progression. Recently, various groups tried to eliminate the most abundant cells in the stroma, the so-called cancer associated fibroblasts (CAFs), but they achieved the opposite effect to that expected: the tumor continued to progress with even greater aggressiveness. The interpretation of this result was that some of the cells eliminated could have anti-tumorigenic functions.
Therefore, scientists from the CNIO's Experimental Oncology Group have focused their work on identifying a stromal cell population that fosters tumor growth, to later discover why they have this capacity and reverse it. The strategy to achieve the latter is innovative, because instead of eliminating these stromal cells which help the tumor, the objective has been their selective reprogramming.
As Carmen Guerra, one of the lead scientists, and Magdolna Djurec, first author of the work, explain "there are now many groups looking into the relationship of the stroma and tumor growth, with the hope of finding new therapeutic strategies. We have seen that eliminating stromal cells may have a negative effect, so our approach is to reprogram the stroma instead of eliminating it. It is an innovative strategy".
The scientists focused on a subpopulation of fibroblasts which are known to play a role in inflammation -because inflammation fosters tumor growth-. Their first task was to analyse all of the genes that are differentially expressed in the stromal fibroblasts of the tumor, the CAFs, in comparison with the fibroblasts of healthy pancreatic tissue. Their hypothesis was that the possible genes responsible for the pro-tumor role of the CAFs would be expressed at high levels only in these fibroblasts, and not in fibroblasts of the healthy tissue.
The analysis revealed that the Saa3 gene is responsible for CAFs helping tumor cells to progress. When the scientists eliminated the expression of this gene in the CAFs, these cells behaved like normal fibroblasts, as they lost the ability to help the tumor cells to progress. Scientists had managed to "reprogram" these cells, which had been stripped of their pro-tumor properties.
Therefore, "this finding may represent a future therapeutic strategic to combine with other strategies, such as immunotherapy, chemotherapy or inhibitors against specific signalling routes of the tumor cells". However, "it opens the door to new research in many laboratories aimed at reprogramming the stroma instead of eliminating it", added Djurec.
It is still too early to think about its clinical application, but the work reveals a new genetic target on which to look for new possible therapeutic strategies.
In human samples of pancreatic cancer, the scientists have identified the same population of 'pro-tumor' fibroblasts and have observed that when the SAA1 gene (the human version of Saa3) is overexpressed, the prognostic for the patients is far worse.
This result is possibly the first of several, because scientists are still studying the role of other genes of potential relevance found in the comparative expression analysis of the CAFs and normal fibroblasts.