Abstract
Despite progresses in diagnosis and treatment, pancreatic cancer continues to have the worst prognosis of all solid malignant tumors. Recent evidences suggest that the metastasis-promoting protein S100P stimulates pancreatic tumor proliferation, survival, invasion and metastasis progression through extracellular functions. Moreover, its expression is strongly correlated with poor prognosis in patients with several types of cancer although the entire molecular mechanism responsible for the diverse biological functions is not fully understood. We showed that extracellular S100P stimulates pancreatic carcinoma BxPC3 cell line by promoting cell proliferation. We also demonstrated that S100P induces, in this cell line, the phosphorylation of IκBα and the secretion of matrix metalloproteinase 9 (MMP-9). In addition, treatment with S100P protected cells from injuries induced by the cytotoxic agent Gemcitabine. On the basis of these results, we developed function-blocking anti-S100P monoclonal antibodies (mAbs) that abolished all of its in vitro activities. Furthermore, in vivo treatment with the candidate 2H8 antibody decreased tumor growth and liver metastasis formation in a subcutaneous and orthotopic BxPC3 tumor model. We conclude here that a therapeutic strategy blocking the extracellular activity of S100P by means of specific mAbs could be an attractive therapeutic approach as a single agent or in combination with target-directed or chemotherapeutic drugs to treat pancreatic cancer.
Highlights
Pancreatic adenocarcinoma is one of the most lethal human cancers with a 5-year survival of less than 5%.1 Because of the difficulty in the detection at an early stage, the majority of tumors are either locally advanced or metastatic upon diagnosis
100 nM of S100P was incubated with monoclonal antibodies (mAbs) against S100P block the induction of cell proliferation mediated by extracellular S100P
To further extend these studies and to find more effective and specific inhibitors, we focused our work abolished the increase in cell proliferation induced by S100P (Figure 1c)
Summary
Pancreatic adenocarcinoma is one of the most lethal human cancers with a 5-year survival of less than 5%.1 Because of the difficulty in the detection at an early stage, the majority of tumors are either locally advanced or metastatic upon diagnosis. Pancreatic adenocarcinoma is one of the most lethal human cancers with a 5-year survival of less than 5%.1. Because of the difficulty in the detection at an early stage, the majority of tumors are either locally advanced or metastatic upon diagnosis. Pancreatic tumors show a high aggressive nature invading mainly regional lymph nodes and liver, and less often the lungs and visceral organs.[2] This high metastatic potential associated with a strong chemoresistance, turns pancreatic carcinoma into one of the most deadly cancer types. In the last two decades, strategies including surgery, radiation and chemotherapy, have failed to improve long-term survival.[3] The current standard of treatment, the nucleoside analog Gemcitabine, prolongs survival by only several months. Recent efforts have focused on the application of novel targeted agents based on a better understanding of the mechanisms involved in tumor progression
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