Abstract
The threatening notoriety of pancreatic cancer mainly arises from its negligible early diagnosis, highly aggressive progression, failure of conventional therapeutic options and consequent very poor prognosis. The most important driver genes of pancreatic cancer are the oncogene KRAS and the tumor suppressors TP53, CDKN2A, and SMAD4. Although the presence of few drivers, several signaling pathways are involved in the oncogenesis of this cancer type, some of them with promising targets for precision oncology. Pancreatic cancer is recognized as one of immunosuppressive phenotype cancer: it is characterized by a fibrotic-desmoplastic stroma, in which there is an intensive cross-talk between several cellular (e.g., fibroblasts, myeloid cells, lymphocytes, endothelial, and myeloid cells) and acellular (collagen, fibronectin, and soluble factors) components. In this review; we aim to describe the current knowledge of the genetic/biological landscape of pancreatic cancer and the composition of its tumor microenvironment; in order to better direct in the intrinsic labyrinth of this complex tumor type. Indeed; disentangling the genetic and molecular characteristics of cancer cells and the environment in which they evolve may represent the crucial step towards more effective therapeutic strategies
Highlights
Pancreatic cancer (PC) is perhaps the most lethal among solid tumors worldwide; incidence varies between different countries, PC is the seventh leading cause of global cancer-relatedCells 2020, 9, 309; doi:10.3390/cells9020309 www.mdpi.com/journal/cellsCells 2020, 9, 309 deaths in industrialized countries, the fourth in Italy, and the third in the United States of America [1,2,3].Long-term survival is poor, with a five-year survival rate ranging from 5% to 8% [3]
The KRAS is an oncogene located on chromosome 12, and is the most frequently mutated gene in PC (>90% of cases); the vast majority of activating mutations occurs at codons 12, 13, or 61 [23,24,25,26,27]
The PC variant with osteoclast-like giant cells is enriched for mutations in the SERPINA3 oncogene, its peculiar morphological aspect has been mainly linked to its specific inflammatory background rather than its genetic profile, which is quite overlapping to conventional PC [57]
Summary
Pancreatic cancer (PC) is perhaps the most lethal among solid tumors worldwide; incidence varies between different countries, PC is the seventh leading cause of global cancer-related. 2–3 years in the majority of cases As highlighted above, such PC unique aggressiveness is due to both specific genetic and molecular traits (acquired through either a stepwise or a chromothripsis-mediated simultaneous loss of multiple tumor suppressors and gain of multiple oncogenes), but to complex interactions with a generally obstructive and immunosuppressive tumor microenvironment (TME), which confer a highly malignant phenotype, as well (Figure 1) [5,6]. Even the combination of therapies simultaneously targeting multiple crosstalking pathways has failed to confer clinical benefit in the absence of predictive biomarkers able to identify patients who will most likely respond to specific therapeutic combinations. This is well exemplified by the recent failure of a theoretically rational combination of MEK and AKT inhibitors [9]. The molecular mechanisms of such interactions are only beginning to be elucidated and the Ariadne’s string linking specific tumor genetic/molecular background(s), to the production of specific sets of soluble factors and to the formation of an obstructive and immune suppressive TME will need to be precisely identified to develop new and effective therapeutic strategies to defeat such an aggressive and therapy resistant disease
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