KRAS proto-oncogene mutations have been detected in 92% of PDAC and are already detectable in precursor lesions, including early preinvasive intraepithelial neoplasia. Among the numerous referenced alterations, KRAS, CDKN2A, TP53, and SMAD4 are the four most frequently mutated genes. Pancreatic carcinogenesis is a multi-stage process resulting primarily from the accumulation of genetic alterations (average of 63 mutations per patient) in the somatic DNA of normal cells as well as inherited mutations ( 7). PanIN lesions are classified in different grades, from PanIN1A to PanIN3, characterized by the evolution of epithelial cell morphology ( Figure 1). This metaplastic process called acinar-to-ductal metaplasia (ADM), is observed during acute and chronic pancreatitis and may represent the initial step toward the formation of pancreatic intraepithelial neoplasia (PanIN), which may then progress to PDAC. Therefore, the discovery of new therapeutics and/or earlier detection of the disease before the onset of signs and symptoms is mandatory to improve patient survival rate.Īcinar cells are the predominant cell type in the pancreas and present an intrinsic plasticity enabling them to perform metaplasia to ductal-like cells. Before or after surgery, or for unresectable tumors, various treatments including chemotherapeutic agents (gemcitabine, nab-paclitaxel, 5-fluorouacil, or FOLFIRINOX) and radiotherapy are generally used, but demonstrate little improvement of patient survival ( 4– 6). Upon cancer detection, resection is possible in 10–20% of the cases, depending on tumor stage, and localization. This poor survival is mainly inherent to the fact that this cancer evolves with few specific symptoms and is therefore mostly diagnosed at an advanced stage when the cancer presents a very aggressive behavior ( 4). However, the fatal outcome of this disease is almost inevitable which consequently ranks this cancer site as the most devastating one. Pancreatic cancer is relatively rare and represents 2.5% of all cancers worldwide in 2018 ( 1). Attention will be paid to Tenascin-C, a matrix glycoprotein commonly upregulated during cancer that participates to PDAC progression and thus contributes to poor prognosis. In this review, we will summarize the current state of knowledge in the field by focusing on TME composition to understand how this specific compartment could influence tumor progression and resistance to therapies. Initially ignored, the Tumor MicroEnvironment (TME) is now the subject of intensive research related to PDAC treatment and could contain new therapeutic targets. Altogether, these combined features make access to cancer cells almost impossible for conventional chemotherapeutics and new immunotherapeutic agents, thus contributing to the fatal outcomes of the disease.
This malignancy is characterized by an extremely dense stroma deposition around lesions, accompanied by tissue hypovascularization and a profound immune suppression.
Pancreatic tumors progress with few specific symptoms and are thus at an advanced stage at diagnosis in most patients. This specific cancer is a devastating malignancy with an extremely poor prognosis, as shown by the 5-years survival rate of 2–9%, ranking firmly last amongst all cancer sites in terms of prognostic outcomes for patients. Among the different types of pancreatic cancers, Pancreatic Ductal Adenocarcinoma (PDAC) is by far the most represented one with an occurrence of more than 90%. Pancreatic cancer is the seventh leading cause of cancer-related deaths worldwide and is predicted to become second in 2030 in industrialized countries if no therapeutic progress is made. 2Cancer Research Center of Lyon, UMR INSERM 1052, CNRS 5286, Lyon, France.1Laboratoire de Biologie Tissulaire et Ingénierie Thérapeutique (LBTI), UMR CNRS 5305, Université Lyon 1, Institut de Biologie et Chimie des Protéines, Lyon, France.Sophie Liot 1 †, Jonathan Balas 1 †, Alexandre Aubert 1, Laura Prigent 1, Perrine Mercier-Gouy 1, Bernard Verrier 1, Philippe Bertolino 2, Ana Hennino 2, Ulrich Valcourt 1 and Elise Lambert 1 *
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