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The differentiation of pancreatic tumor-initiating cells by vitronectin can be blocked by cilengitide
Stephanie M Cabarcas1, Lei Sun, Lesley Mathews
1Cancer Stem Cell Section, Laboratory of Cancer Prevention, Center for Cancer Research, Frederick National Laboratory for Cancer Research, Frederick, MD, USA. cabarcas002@gannon.edu
Objective:
Pancreatic cancer is a leading cancer type and its molecular pathology is poorly understood. The only potentially curative therapeutic option available is complete surgical resection; however, this is inadequate as most of the patients are diagnosed at an advanced or metastatic stage. Tumor-initiating cells (TICs) constitute a subpopulation of cells within a solid tumor that sustain tumor growth, metastasis, and chemo/radioresistance. Within pancreatic cancer, TICs have been identified based on the expression of specific cell surface markers.
Methods:
We use a sphere formation assay to enrich putative TICs and use human serum as a driver of differentiation. We demonstrate by using specific blocking reagents that we can inhibit the differentiation process and maintain TIC-associated markers and genes.
Results:
We can induce differentiation of pancreatospheres with the addition of human serum, and we identified vitronectin as an inducer of differentiation. We inhibit differentiation by human serum using an arginine-glycine-aspartate-specific peptide, which is Cilengitide; hence, demonstrating this differentiation is mediated via specific integrin receptors.
Conclusions:
Overall, our studies further the definition of pancreatic TICs and provide further insight into both the maintenance and differentiation of this lethal population.
Insights
Researchers identified vitronectin as a key factor driving pancreatic cancer tumor-initiating cell (TIC) differentiation. Blocking this process with Cilengitide offers potential therapeutic strategies against this lethal cancer.
Area of Science:
- Oncology
- Cell Biology
- Biochemistry
Background:
- Pancreatic cancer is a significant cause of cancer-related mortality with poorly understood molecular mechanisms.
- Complete surgical resection is the only curative option, but is often not feasible due to late-stage diagnosis.
- Tumor-initiating cells (TICs) drive tumor growth, metastasis, and treatment resistance in pancreatic cancer.
Purpose of the Study:
- To further define pancreatic cancer TICs and understand their maintenance and differentiation.
- To identify factors that regulate the differentiation of pancreatic TICs.
Main Methods:
- Sphere formation assays were used to enrich for pancreatic TICs.
- Human serum was utilized as a differentiation-inducing agent.
- Specific blocking reagents, including an RGD-specific peptide (Cilengitide), were employed to inhibit differentiation.
Main Results:
- Human serum induced differentiation of pancreatospheres, a process mediated by integrin receptors.
- Vitronectin was identified as a specific inducer of this serum-mediated differentiation.
- Cilengitide effectively inhibited serum-induced differentiation, maintaining TIC markers.
Conclusions:
- These findings enhance the definition of pancreatic TICs and their characteristics.
- Vitronectin and integrin signaling represent potential therapeutic targets for controlling pancreatic TIC differentiation.
- Understanding TIC differentiation is crucial for developing effective treatments for pancreatic cancer.
