Abstract
Although trastuzumab (Herceptin) has substantially improved the overall survival of patients with mammary carcinomas, even initially well-responding tumors often become resistant. Because natural killer (NK) cell-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) is thought to contribute to the therapeutic effects of trastuzumab, we have established a cell culture system to select for ADCC-resistant SK-OV-3 ovarian cancer and MCF7 mammary carcinoma cells. Ovarian cancer cells down-regulated HER2 expression, resulting in a more resistant phenotype. MCF7 breast cancer cells, however, failed to develop resistance in vitro. Instead, treatment with trastuzumab and polyclonal NK cells resulted in the preferential survival of individual sphere-forming cells that displayed a CD44(high)CD24(low) "cancer stem cell-like" phenotype and expressed significantly less HER2 compared with non-stem cells. Likewise, the CD44(high)CD24(low) population was also found to be more immunoresistant in SK-BR3, MDA-MB231, and BT474 breast cancer cell lines. When immunoselected MCF7 cells were then re-expanded, they mostly lost the observed phenotype to regenerate a tumor cell culture that displayed the initial HER2 surface expression and ADCC-susceptibility, but was enriched in CD44(high)CD24(low) cancer stem cells. This translated into increased clonogenicity in vitro and tumorigenicity in vivo. Thus, we provide evidence that the induction of ADCC by trastuzumab and NK cells may spare the actual tumor-initiating cells, which could explain clinical relapse and progress. Moreover, our observation that the "relapsed" in vitro cultures show practically identical HER2 surface expression and susceptibility toward ADCC suggests that the administration of trastuzumab beyond relapse might be considered, especially when combined with an immune-stimulatory treatment that targets the escape variants.
Highlights
The Her-2/neu (c-erbB2, HER2) proto-oncogene belongs to a family of four transmembrane receptor tyrosine kinases that mediate cell growth, differentiation, and survival [1]
To assess the effect of trastuzumab on the natural killer (NK) cell–mediated lysis of HER2expressing ovarian cancer cells, luciferase-transfected SK-OV-3 cells were treated with polyclonal NK cells in the presence of human control IgG and/or trastuzumab at the indicated concentration
Because NK cell–mediated antibody-dependent cell-mediated cytotoxicity (ADCC) was shown to be important for the in vivo function of the antibody [18], we wondered whether the failure to respond to trastuzumab might be related to tumor immune escape, especially because the continuous confrontation with the host immune system is likely to trigger some kind of ‘‘immunoediting’’ [29]
Summary
The Her-2/neu (c-erbB2, HER2) proto-oncogene belongs to a family of four transmembrane receptor tyrosine kinases that mediate cell growth, differentiation, and survival [1]. Trastuzumab (Herceptin, Genentech), a humanized monoclonal antibody (rhumAb 4D5) directed against the extracellular domain of HER2, improves disease-free and overall survival in patients with early, metastasized, or recurrent HER2-positive breast cancer significantly [6, 7]. The far greater problem is that a significant number of patients with HER2-overexpressing tumors do not respond to trastuzumab [6] or eventually develop resistance after a good initial response [9]. Trastuzumab does not play a significant role because HER2 overexpression is rare and the objective response rates (7.3%) are low among HER2-overexpressing ovarian cancer patients [10]. Data regarding the combination of trastuzumab with chemotherapy are scarce for these patients
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