Determining the role of PI3K-β and PI3K-δ in Canine Hemangiosarcoma and Human Angiosarcoma.
Gutwillig, Megan.
2019
-
Neoplastic disease
arising from endothelial cells occurs spontaneously in humans (angiosarcoma, AS) and pet
dogs (hemangiosarcoma, HSA) and in both species exhibits aggressive biologic behavior
including early metastasis and chemotherapy resistance. While AS is a rare cancer, with
300-500 new diagnoses per year, HSA is far more common, affecting over 50,000 pet dogs
yearly. Molecular and ... read moregenetic studies have shown that both AS and HSA exhibit
dysregulation of the PI3K/AKT/mTOR pathway driven by PIK3CA mutations and PTEN
mutations/deletions. While the contribution of PI3K-α to pathway activation has
been interrogated in AS/HSA, the influence of signaling mediated by the other PI3K class
I catalytic isoforms (PI3K-β and δ) remains unknown. We determined that of
the 4 canine and 2 human cell lines studied, all express PI3K-β and all but one of
the human cell lines express PI3K-δ. This was unexpected as PI3K-δ is
typically only expressed in cells of hematopoietic/lymphoid origin. The canine HSA cell
lines exhibited constitutive pathway activation despite serum starvations and both the
canine and human HSA/AS cell lines were sensitive to treatment with a pan-PI3K
inhibitor, resulting in decreased cell proliferation. However, isoform specific
inhibitors had little effect, suggesting that the tumor cells rely upon multiple PI3K
isoforms for survival and proliferation. Knockdown of PI3K-β and δ
expression of in the Dal-4 and EFB canine HSA cell lines had no effect on cell
proliferation or migration through trasnwells; however, the EFB cell line exhibited a
marked decrease in invasive capacity following PIK3CB knockdown. In conclusion, we
determined that the PI3K/AKT/mTOR pathway has a role in driving sustained proliferation
of HSA/AS cells, with multiple PI3K isoforms contributing to this effect. Additionally,
the PI3K-β isoform may play a role in supporting cell invasion, a finding that
warrants further exploration with respect to isoform specific biologic
effects.
Thesis (M.S.)--Tufts University, 2019.
Submitted to the Dept. of Genetics.
Advisor: Cheryl London.
Committee: Philip Hinds, Karl Munger, and Rachel Buchsbaum.
Keywords: Genetics, and Cellular biology.read less - ID:
- zg64v0479
- To Cite:
- TARC Citation Guide EndNote
