ABSTRACT
Within the tumor, malignant and stromal cells support each other by secreting a wide variety of growth factors and cytokines, allowing tumor growth and disease progression. The identification and regulation of those key factors in this crosstalk has opened the opportunity to develop new therapeutic strategies that not only act on the tumor cells but also on the stroma. Among these factors, S100A7 protein has gained interest in the last years. With key roles in cell motility its expression correlates with increased tumor growth, angiogenesis and metastatic potential. This work aims to deepen in the role played by extracellular S100A7 in the tumor microenvironment, offering a new integrative insight of its mechanism of action on each cellular compartment (tumor, endothelial, immune and fibroblast). As a result, we demonstrate its implication in cell migration and invasion, and its important contribution to the formation of a proinflammatory and proangiogenic environment that favors tumor progression and metastasis. Furthermore, we define its possible role in the pre-metastatic niche formation. Considering the relevance of S100A7 in cancer progression, we have developed neutralizing monoclonal antibodies, reporting for the first time the proof of principle of this promising therapeutic strategy for cancer treatment.
Subject(s)
Neoplasms/metabolism , Neovascularization, Pathologic/metabolism , S100 Calcium Binding Protein A7/metabolism , Xenograft Model Antitumor Assays , Animals , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/pharmacology , Antibodies, Neutralizing/immunology , Antibodies, Neutralizing/pharmacology , Cell Line, Tumor , Cell Movement/drug effects , Cells, Cultured , Female , Humans , Mice, Inbred BALB C , Mice, Nude , Neoplasms/blood supply , Neoplasms/drug therapy , Neovascularization, Pathologic/prevention & control , Recombinant Proteins/pharmacology , S100 Calcium Binding Protein A7/genetics , S100 Calcium Binding Protein A7/immunology , Tumor Microenvironment/drug effectsABSTRACT
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.
