From Genetic Alterations to Tumor Microenvironment: The Ariadne’s String in Pancreatic Cancer

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

Morphologic and Molecular Landscape of Pancreatic Cancer Variants as the Basis of New Therapeutic Strategies for Precision Oncology

“…In recent years, precision oncology has undoubtedly been one of the most important revolutions in clinical practice and has significantly improved the quality and life expectancy of cancer patients. Despite the attempt to untie the Ariadne’s string connecting genetic/molecular landscape of pancreatic cancer cells with their complex TME, PDAC and its variants remain the deadliest tumors in the Western world [ 5 ]. Furthermore, the classification of PDAC variants according histopathological characteristics still do not help clinicians in the best treatment choice for personalized medicine.…”

“…Indeed, the cornerstone in the treatment of pancreatic cancer is still the aggressive and cytotoxic chemotherapy, as target therapies met with limited clinical success, mostly due to the absence of validated prognostic/predictive biomarker(s) [ 4 ]. The reason behind this failure is due, at least in part, to the complexity of the pancreatic tumor for both its genetic status and bidirectional interactions with the tumor microenvironment (TME) [ 5 ]. Indeed, pancreatic cancer cells are characterized by a hypermutated landscape, with four most commonly mutated genes: the Kirsten rat sarcoma ( KRAS ) oncogene, the tumor suppressor protein 53 ( TP53 ), the cyclin dependent kinase inhibitor 2A ( CDKN2A ), and the SMAD family member 4 ( SMAD4 ) tumor suppressor genes [ 6 ].…”

Visualization Analysis of Publication Trends and Research Hotspots on the Tumor Microenvironment of Pancreatic Cancer Between 2010 and 2020: a Bibliometric Study

“…The TME is composed of tumor cells, stromal cells, and extracellular components such as interstitial tissues near tumor cells. The TME provides conditions for the occurrence, development, invasion, and metastasis of PC [4]. Institutions and researchers that have aimed at targeting the crosstalk between tumor cells and the TME continue to offer hope for the treatment of PC [5].…”

A phase II study of liposomal irinotecan with 5-fluorouracil, leucovorin and oxaliplatin in patients with resectable pancreatic cancer: the nITRO trial

“… 1 The poor prognosis for patients affected by this disease could be mainly attributed to the limited efficacy of available systemic treatments, and to the early metastatic behavior demonstrated along the process of tumor progression that makes de facto pancreatic cancer a systemic disease at the time of diagnosis. 2 – 6 More than 80% of patients present, indeed, with a locally advanced or metastatic disease, 7 and even among patients with apparently localized disease who undergo surgery and postoperative therapy, metastatic recurrence remains extremely common. 8 …”