Xenograft Models of Herceptin Resistance in Breast Cancer

سال انتشار: 1394
نوع سند: مقاله کنفرانسی
زبان: انگلیسی
مشاهده: 492

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NASTARANCANSER01_011

تاریخ نمایه سازی: 26 شهریور 1395

چکیده مقاله:

Herceptin (Trastuzumab, TZMB) is a humanized monoclonal antibody used to treat HER2+ breastcancer (BC). Patient resistance against TZMB therapyis a major clinical issue to be addressed.Infiltrating fibroblasts secrete glial cell line-derived neurotrophic factor (GDNF) to the tumormicroenvironment. Besides, GDNF receptor RET contributes to hormone resistance in BC bycrosstalking with HER receptors.We hypothesized that GDNF can promote a bypassing mechanism toconfront TZMB resistance by inducing RET-HER2 crosstalks via non-receptor tyrosine kinase SRC.We created animal models of sensitive and resistant human tumors by collecting tumor samples fromthree patients bearing HER2-, HER2+/TZMBSensitive (S)and HER2+/TZMBResistance (R)BC tumors, andinjectingthe samplesinto SCID/nude mice. The generatedtumor models were treated first with TZMBfor 4 weeks and then with TZMB+GDNF for the second 4-week period. Three distinct cell lines wereisolated from these three xenograft models in order to facilitate examination ofpossible mechanismsbehind TZMB resistance. Dose responses were determined based on which tumor cell treatment andco-treatment studies were designed and carried out. Cell survival and apoptosis rates were examined.The sensitive xenograft tumor but not the HER2- or resistant ones shrunk upon treatment withTZMB.In contrast, GDNF induced sensitive tumor growth and effectively prevented TZMB frominducing apoptosis. We are currently using these cell lines to examine if GDNF can confrontTZMBmediatedapoptosis in sensitive tumors and activate alternative growth pathways inBC tumors that arenot responding to TZMB therapy. GDNF potentially abrogates TZMB action on inducing BC cellapoptosis and can activate alternative routes for growth inTZMB-resistant BC cells.Xenograft modelsprovide informative insights into cell-molecular mechanisms behind antibody resistance among BCpatients and hold promise for shapingfuture directionsfor overcoming this clinically critical issue.

نویسندگان

Mossa Gardaneh

Division of Stem Cells and Regenerative Medicine, Faculty of Medical Biotechnology, National Institute ofGenetic Engineering and Biotechnology (NIGEB), Tehran, I.R. Iran

Sahar Shojaei

Division of Stem Cells and Regenerative Medicine, Faculty of Medical Biotechnology, National Institute ofGenetic Engineering and Biotechnology (NIGEB), Tehran, I.R. Iran