Abstract
Pancreatic cancer (PC) is the third leading cause of adult cancer mortality in the United States. The poor prognosis for patients with PC is mainly due to its aggressive course, the limited efficacy of active systemic treatments, and a metastatic behavior, demonstrated throughout the evolution of the disease. On average, 80% of patients with PC are diagnosed with metastatic disease, and the half of those who undergo surgery and adjuvant therapy develop liver metastasis within two years. Metastatic dissemination is an early event in PC and is mainly attributed to an evolutionary biological process called epithelial-to-mesenchymal transition (EMT). This innate mechanism could have a dual role during embryonic growth and organ differentiation, and in cancer progression, cancer stem cell intravasation, and metastasis settlement. Many of the molecular pathways decisive in EMT progression have been already unraveled, but little is known about the causes behind the induction of this mechanism. EMT is one of the most distinctive and critical features of PC, occurring even in the very first stages of tumor development. This is known as pancreatic intraepithelial neoplasia (PanIN) and leads to early dissemination, drug resistance, and unfavorable prognosis and survival. The intention of this review is to shed new light on the critical role assumed by EMT during PC progression, with a particular focus on its role in PC resistance.
Highlights
According to the American Cancer Society, pancreatic cancer (PC) is ahead of breast cancer as the third leading cause of cancer-related death in the United States, and is predicted to become the second leading cause of cancer-related death by 2020 [1,2]
We summarize the role of epithelial-to-mesenchymal transition (EMT) in the context of drug resistance and metastasis in PC, with a special focus on inflammation
More recently we demonstrated that combined inhibition of proinflammatory interleukin (IL) 1, CXCR1/2, and transforming growth factor (TGF)-β signaling pathways might reverse this anti-vascular endothelial growth factor (VEGF) resistance, reversing epithelial–mesenchymal transition and inhibiting CD11b+
Summary
According to the American Cancer Society, pancreatic cancer (PC) is ahead of breast cancer as the third leading cause of cancer-related death in the United States, and is predicted to become the second leading cause of cancer-related death by 2020 [1,2]. Since the late 1990s gemcitabine has represented the standard of care for advanced PC, it does not show a drastic improvement in median survival rate [4] This is mainly explained by the unique chemoresistance of PC cells [5]. The histology and the genetic of pancreatic carcinogenesis have been well described [6], the molecular mechanisms that promote the metastatic spread of PC are less clear [7] These mechanisms include the ability of cancer cells to break away from extracellular matrix (ECM) and to overcome apoptosis process. This behavior has been associated with an early epithelial-to-mesenchymal transition (EMT) in premalignant lesions [8]. We summarize the role of EMT in the context of drug resistance and metastasis in PC, with a special focus on inflammation
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