Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia

Abstract

Antiangiogenic therapy has been thought to hold significant potential for the treatment of cancer. However, the efficacy of such treatments, especially in breast cancer patients, has been called into question, as recent clinical trials reveal only limited effectiveness of antiangiogenic agents in prolonging patient survival. New research using preclinical models further suggests that antiangiogenic agents actually increase invasive and metastatic properties of breast cancer cells. We demonstrate that by generating intratumoral hypoxia in human breast cancer xenografts, the antiangiogenic agents sunitinib and bevacizumab increase the population of cancer stem cells. In vitro studies revealed that hypoxia-driven stem/progenitor cell enrichment is primarily mediated by hypoxia-inducible factor 1α. We further show that the Akt/β-catenin cancer stem cell regulatory pathway is activated in breast cancer cells under hypoxic conditions in vitro and in sunitinib-treated mouse xenografts. These studies demonstrate that hypoxia-driven cancer stem cell stimulation limits the effectiveness of antiangiogenic agents, and suggest that to improve patient outcome, these agents might have to be combined with cancer stem cell-targeting drugs.antiangiogenesis | HIF-1α

Role of vascular normalization in benefit from metronomic chemotherapy

“…We made the distinction, however, that whereas CC proliferation increases with oxygen levels, CSC and ICC proliferation increases under hypoxic conditions. Therefore, we assume that in hypoxic conditions, the proliferation of CSCs and ICCs increases inversely with oxygen concentration, so that as oxygen concentration approaches 0, the proliferation rate is twice the rate at normal oxygen concentration (34).…”

“…S14). Finally, we assumed that the activity of immune cells is affected by tumor oxygenation (6,34,61). Owing to a lack of studies that directly relate oxygen levels to the data on the activity of NK or CD8 + T cells incorporated in our model, we used values from the range reported by de Pillis et al (53), whose model focuses on the action of NK and CD8 + T cells, with values of the model parameters specified by comparing model predictions with preclinical and clinical data.…”

“…Increases in drug levels result in more efficient killing of CCs, CSCs, and ICCs (57,58). Higher oxygen concentrations accelerate the proliferation rates of CCs and the activity of immune cells, whereas hypoxia favors CSC and ICC proliferation (33,34,61). An increase in immune response results in more efficient killing of all cancer cells (53).…”

“…1, drug delivery and tumor oxygenation depend on the functional vascular density (i.e., tumor perfusion). Tissue oxygenation favors the activity of immune cells and the proliferation rate of CCs, whereas hypoxia promotes CSC and ICC phenotypes (34).…”

Tumor Blood Vessels and Vasculogenic Mimicry – Current Knowledge and Searching for New Cellular/Molecular Targets of Anti-Angiogenic Therapy

“…In breast cancer, about 200 CSCs is per 500 thousand of cancer cells, and in glioblastoma this proportion is 100 CSCs per 100 thousand tumor cells. Conley and co-workers [15] show that Bevacizumab, as well as Sunitinib induces the increase of CSCs amount in xenografts of breast cancer, via signalling pathway Akt/β-catenin, which is responsible for CSCs self-renewal. The increase of aldehyde dehydrogenase (ALDH) expression (marked by Aldefluor + ) proves the increase of CSCs.…”