Retain
- Cellular senescence, an irreversible cessation mechanism of the cell cycle, plays a complex role in pancreatic canal adenocarcinoma, influencing both tumorigerisis and therapeutic resistance.
- Senescent cells secrete factors that can promote tumor and immune escape, while potentially contributing to resistance to treatments.
Methodology
- An in -depth review of the scientific literature was carried out to explore the complex role of senescence in pancreatic canal adenocarcinoma, by focusing particularly on its dual nature during tumorigenesis and therapeutic resistance.
- The researchers have analyzed the recent molecular mechanisms involved in senescence exhaust and its impact on tumor progression, with particular attention paid to the secretory phenotype associated with senescence.
- The analysis has integrated studies on tumor microenvironment and its influence on chemoresistance, in particular by examining the role of senescent stromal cells.
Main results
- Senegascence exhaust, facilitated by the inactivation of TP53 and P16 in respectively 70 % and 80 to 95 % of cases of pancreatic canal adenocarcinoma, plays a crucial role in tumor progression.
- Gemcitabine induces a state of senescence in resistant pancreatic cancer cells, which allows them to retention in the cell cycle and contributes to therapeutic resistance.
- Fibroblasts associated with senescent cancer, representing approximately 20 % of fibroblasts in premaling lesions and pancreatic cancer, modulate the activity of macrophages and promote immune escape.
- The combined inhibition of Mek and CDK4/6 induces cell senescence and improves tumor vascularization, thus increasing the infiltration of T lymphocytes and therapeutic efficiency.
In practice
Characterized by a dark prognosis and an often late diagnosis, pancreatic canary adenocarcinoma represents approximately 85 % of cases of exocrine cancer of the pancreas. The complexity of the tumor molecular landscape, combined with late detection and significant heterogeneity at cellular and microenvironmental levels, underpins its notorious resistance to therapeutic interventions. Only 10 to 20 % of patients are eligible for surgical resection, which leaves systemic chemotherapy as a standard treatment for the majority of cases. Cellular senescence, initially described as an irreversible cessation mechanism of the cell cycle, emerges as a complex process with significant implications in the biology of pancreatic cancer. Senescent cells, characterized by growth stop and resistance to apoptosis, remain metabolically active and secrete pro-tumorigen factors that can modulate tumor microenvironnement.
According to the authors, « An effective approach to use senescence in the treatment of the PDAC would first administer an agent inducing senescence to stop tumor progression, followed by the targeted elimination of the resulting senescent tumor and stromal cells, often called the “One-Two Punch” […] The combination of Mek and CDK4/6 inhibitors has proven to promote the induction of senescence, vascularization and endothelial activation which improved the infiltration of T lymphocytes and the subsequent elimination of tumor cells ».
Main limitations
The authors highlight the complexity of the interactions between the signaling pathways in the progression of pancreatic cancer, which makes it difficult to identify precise identification of the senescence exhaust mechanisms. In addition, the paradoxical nature of the secretory phenotype associated with senescence complicates the development of targeted therapeutic strategies, requiring a prudent approach in the use of senescence inductors.
Funding and interest links
This study was supported by the Bennink Foundation, the Dutch company against cancer – KWF, the European organization for the research and treatment of cancer, Panomic, the Italian association for cancer research and Cost Transpan.
This article was created using several editorial tools, including AI, as part of the process. The editorial team saw this content before its publication.
