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Type I collagen and divalent cation shifts disrupt cell-cell adhesion, increase migration, and decrease PTHrP, IL-6,
John J Grzesiak1, Kathy C Smith, Cheryl Chalberg
1Department of Surgery, University of California, San Diego and Veterans Affairs, San Diego Healthcare System, San Diego, CA 92161, USA.
International Journal of Gastrointestinal Cancer
|May 25, 2006
Summary
Type I collagen adhesion in pancreatic cancer cells disrupts cell-cell junctions, increasing migration and decreasing key cytokine expression. This impacts cell adhesion and signaling pathways in cancer progression.
Area of Science:
- Cell Biology
- Cancer Research
- Molecular Biology
Background:
- Alpha2beta1 integrin-mediated type I collagen adhesion in FG pancreatic cancer cells reduces parathyroid hormone-related protein (PTHrP), interleukin-6 (IL-6), and interleukin-8 (IL-8) expression.
- This adhesion also decreases E-cadherin and beta-catenin in cell-cell contacts, enhances cell migration, and increases phosphorylation of glycogen synthase kinase 3 (GSK3) and protein kinase B (PKB/Akt).
Purpose of the Study:
- To extend these findings to other pancreatic cancer cell lines.
- To investigate the functional role of E-cadherin-mediated cell-cell adhesion and its downstream effectors in extracellular matrix (ECM)-mediated regulation of PTHrP, IL-6, and IL-8.
Main Methods:
- Standard biochemical techniques were used to analyze ECM-specific differences in E-cadherin and beta-catenin localization, GSK3 and PKB/Akt phosphorylation, haptokinetic cell migration, and cytokine expression.
- Functional studies involved pharmacological inhibitors of GSK3 and PKB/Akt, and elevated Mg2+/Ca2+ ratios to assess effects on cytokine expression.
Main Results:
- Differences in E-cadherin/beta-catenin localization and GSK3/PKB/Akt phosphorylation were observed across multiple pancreatic cancer cell lines.
- These differences correlated with ECM-mediated haptokinesis and cytokine expression, consistent with prior FG cell observations.
- Functional studies indicated that E-cadherin-mediated cell-cell adhesion and downstream signaling pathways are involved in regulating PTHrP, IL-6, and IL-8 expression.
Conclusions:
- Alpha2beta1 integrin-mediated type I collagen adhesion disrupts pancreatic cancer cell-cell adhesion architecture.
- This disruption leads to increased cell migration and decreased expression of PTHrP, IL-6, and IL-8.