The Pancreatic Cancer pathophysiology overview
Pancreatic cancer is renowned for its aggressive nature and poor prognosis, primarily due to its complex underlying pathophysiology. To understand this disease better, it is essential to explore the cellular and molecular mechanisms driving its development and progression. The majority of pancreatic cancers originate from the exocrine component of the pancreas, with pancreatic ductal adenocarcinoma (PDAC) accounting for over 90% of cases.
The process begins with genetic mutations in pancreatic cells, often involving key oncogenes and tumor suppressor genes. The most common genetic alteration in PDAC is the mutation of the KRAS gene, which occurs in over 90% of cases. This mutation leads to constitutive activation of signaling pathways that promote uncontrolled cell proliferation, resistance to apoptosis, and enhanced survival. Alongside KRAS mutations, inactivation of tumor suppressor genes such as TP53, CDKN2A (p16), and SMAD4 further facilitates malignant transformation by impairing cell cycle regulation, DNA repair, and apoptotic pathways.
These genetic changes set the stage for a multistep carcinogenesis process characterized by a progression from benign pancreatic intraepithelial neoplasia (PanIN) to invasive carcinoma. During this progression, the tumor microenvironment plays a crucial role. As the tumor develops, it induces a desmoplastic stroma—an abundant fibrous tissue surrounding the tumor cells—that not only provides structural support but also promotes tumor growth and invasion. This stromal reaction involves activation of pancreatic stellate cells, which secrete extracellular matrix proteins and cytokines, fostering an environment that shields tumor cells from immune surveillance and impedes drug delivery.
The molecular landscape of pancreatic cancer also involves dysregulation of various signaling pathways, including the Wnt/β-catenin, Notch, and Hedgehog pathways. These pathways contribute to maintaining cancer stem cell populations, promoting metastasis, and resisting conventional therapies. Additionally, the tumor’s ability to evade immune detection is partly due to the immunosuppressive microenvironment, which is rich in regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages that inhibit effective anti-tumor immune responses.
Metastasis is a hallmark of pancreatic cancer, significantly influencing patient prognosis. Tumor cells gain invasive capabilities through epithelial-mesenchymal transition (EMT), involving alterations in cell adhesion molecules like E-cadherin and N-cadherin. These changes facilitate detachment from the primary tumor, invasion into surrounding tissues, and dissemination via lymphatic and blood vessels, leading to metastases in the liver, peritoneum, and other organs.
In summary, the pathophysiology of pancreatic cancer is a complex interplay of genetic mutations, stromal interactions, signaling pathway dysregulation, and immune evasion. Understanding these mechanisms is vital for developing targeted therapies and improving diagnosis, management, and outcomes for patients afflicted by this devastating disease.
