Abstract
In this study we evaluated the interaction of pancreatic cancer cells, cancer-associated fibroblasts, and distinct drugs such as α-cyano-4-hydroxycinnamate, metformin, and gemcitabine. We observed that α-cyano-4-hydroxycinnamate as monotherapy or in combination with metformin could significantly induce collagen I deposition within the stromal reaction. Subsequently, we demonstrated that cancer-associated fibroblasts impaired the anti-proliferation efficacy of α-cyano-4-hydroxycinnamate, metformin and gemcitabine. Interestingly, inhibition of autophagy in these fibroblasts can augment the anti-proliferation effect of these chemotherapeutics in vitro and can reduce the tumor weight in a syngeneic pancreatic cancer model. These results suggest that inhibiting autophagy in cancer-associated fibroblasts may contribute to strategies targeting cancer.
Highlights
Despite decades of intensive effort, the 5-years relative survival rate of pancreatic cancer is still only 8% [1]
In order to assess if inhibitors of cell metabolism impair pancreatic cancer cells, 6606PDA cells were treated with 10 mM CHC, 5 mM metformin or both drugs
The present study demonstrates that cancer-associated fibroblasts (CAFs) protect carcinoma cells form chemotherapeutical agents
Summary
Despite decades of intensive effort, the 5-years relative survival rate of pancreatic cancer is still only 8% [1]. One reason might be that these treatment strategies only targeted pancreatic cancer cells, but ignored the abundant desmoplastic stroma around the tumor [2]. This stromal reaction impairs vasculature and functions as a barrier to chemotherapeutics. Subsequent clinical trials demonstrated that reducing fibrosis in addition to a first-line therapy was not beneficial for patients [8]. This suggests that reduction of CAFs is not a good option for cancer therapy. A better option may be to modify specific aspects of interactions between CAFs and carcinoma cells
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