טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentRashed Rula
SubjectThe role of CD24 in Breast cancer progression
DepartmentDepartment of Medicine
Supervisor Professor Emeritus Derek Leroith
Full Thesis textFull thesis text - English Version


Abstract

The pro-tumorigenic effects of the insulin-like growth factor receptor (IGF1R) are well described. IGF1R promotes cancer cell survival, proliferation, prevents apoptosis, and, additionally it was shown that IGF1R levels are significantly elevated in most common human malignancies including breast cancer. However, results from phase 3 clinical trials in unselected patients demonstrated lack of efficacy for anti-IGF1R therapy. These findings suggest that predictive biomarkers are greatly warranted in order to identify patients that will benefit from anti-IGF1R therapeutic strategies.

Using the delivery of shRNA vectors into the Mvt1 cell line, we tested the role of the IGF1R in the development of mammary tumors. Based on CD24 cell surface expression, control and IGF1R-knock down (IGF1R-KD) cells were FACS sorted into CD24- and CD24 subsets and further characterized in-vitro. The tumorigenic capacity of each was determined following orthotopic inoculation into the mammary fat pad of female mice. Tumor cells were FACS characterized upon sacrifice to determine IGF1R effect on the plasticity of these cells' phenotype. Metastatic capacity of the cells was assessed using the tail vein assay.

In this study we demonstrate that down-regulation of the IGF1R, specifically in cancer cells expressing CD24 on the cell surface, affects both their morphology (from mesenchymal-like into epithelial-like morphology) and phenotype in-vitro. Moreover, we demonstrate that IGF1R-KD abolished both CD24 cells capacity to form mammary tumors and lung metastatic lesions.  We found in both cells and tumors a marked up regulation in CTFG and a significant reduction of SLP1 expression in the CD24/IGF-1RKD; tumor suppressor and tumor promoting genes respectively.

Moreover, we demonstrate that the IGF1R is essential for the maintenance of stem/progenitor-like cancer cells and we further demonstrate that IGF1R-KD induces in-vivo differentiation of the CD24 cells toward the CD24- phenotype. This further supports the anti-tumorigenic effects of IGF1R-KD, as we recently demonstrated that these differentiated cells demonstrate significantly lower tumorigenic capacity compared with their CD24 counterparts.

Taken together these findings suggest that CD24 cell surface expression may serve as a valuable biomarker in order to identify mammary tumors that will positively respond to targeted IGF1R therapies.