Posted by: Dan | June 20, 2006

PI3K and Chemotaxis: a comparison of leukocytes and carcinoma cells

There’s an interesting paper out this week on Phosphatidylinositol 3-kinase (PI3K) in G Protein-coupled receptor(GPCR)-induced chemotaxis of MDA-MB-468 Breast Carcinoma Cells: A comparison with Leukocytes.

The premise behind this study is to elucidate the differences between two of the primary classes of autonomously migratory cells in adults – immune and tumor cells, with a focus on PI3K, which has become a focus for polarity and directional migration in motile cells. Uncovering mechanisms of migration that inhibit tumor cell migration, but does not impair immune cell function, has important implications for both oncology and immunology.

Interestingly, Bastian et al. used a three-dimensional collagen-based migration assay that reasonably approximates the in vivo situation, while remaining skeptical of the standard two-dimensional migration assays and their results. Also, they focus on PI3K-related cell migration in the context of GPCR’s, which are useful for understanding the roles of chemokines in chemotaxis, but not the roles of growth factors. Yet, their results do have important implications for understanding chemotaxis and the prospects for specific drug targetting of malignant tumor cells – but they’re confusing results…

The main development in Bastian et al. was that a polarized distribution of PI3K and its antagonistic phosphatases SHIP and PTEN was found in the investigated leukocytes but not in tumor cells. So while PI3K did promote motility (chemokinesis), it did not play a noticeable role in directed behavior (chemotaxis). This finding is in direct opposition to a variety of conclusions, including studies from my own lab here at Cornell – PI3K functions as a polarizer in some cells, but not others. Is this a result of deregulation of some signaling pathways in this cell type, or are there other signaling pathways?

Bastian et al. restate that question as “…if PIP3 [PI3K’s enzymatic product] is not the (sole) second messenger to maintain the polarization in these chemotactically migrating cells, what else could this be?”

And for clinical cancer therapy, they find “…that the GPCR-induced migration of tumor cells can be prevented by the inhibition of the PI3K but only with severe inhibitory side effects on the migration of leukocytes… The authors of this study recommend that further investigations on the involvement of certain PI3K isotypes need to be done, before a clinical use of pharmacologic inhibitors in oncology can be estimated.”

Reference:

  • Phosphatidylinositol 3-Kinase in the G Protein-Coupled Receptor-Induced Chemokinesis and Chemotaxis of MDA-MB-468 Breast Carcinoma Cells: A Comparison with Leukocytes. Bastian P, Posch B, Lang K, Niggemann B, Zaenker KS, Hatt H, Entschladen F. Mol Cancer Res. 2006 Jun; 4(6):411-21. Pubmed

And also out this week on the topic of PI3K:

  • Phosphoinositide 3-Kinase C2{beta} Regulates Cytoskeletal Organization and Cell Migration via Rac-dependent Mechanisms. Katso et al.
  • Inhibition of EGFR/PI3K/AKT cell survival pathway promotes TSA’s effect on cell death and migration in human ovarian cancer cells. Zhou et al.
  • Roles for phosphoinositide 3-kinases, Bruton’s tyrosine kinase, and Jun kinases in B lymphocyte chemotaxis and homing. Ortolano et al.

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