The Effects Of Cellular Senescence In Endothelial Cells On Breast Cancer Development

During early stages of tumorigenic transformation, cells are exposed to various types of stress. In response, cells can undergo senescence to avoid uncontrolled cell divisions and tumor development. Senescent cells are thought to be non-dividing, yet their presence in the tumor lesion, or in the stroma, may influence cells in their environment through cytokine secretion or other means, and thereby exert either tumor-promoting or tumor-suppressing effects. Endothelial cells are an important component of the tumor stroma. These cells affect their environment by delivery of oxygen and nutrients, and also by secretion of growth factors and by immune cell recruitment. Modification of tumor microvasculature function can thereby affect cancer development. Here, we aim to uncover the consequences of senescence in endothelial cells within tumors. To do this, we generated transgenic mice that allow the induction of p16^Ink4A, a main activator of the senescence program, in the vasculature of mice that develop breast cancer. Strikingly, we found that p16^Ink4A activation in blood vessels of developing tumors leads to decreased numbers of proliferating cells in the lesions, without affecting vessel numbers. This suggests that endothelial senescence causes reduced support of tumor growth by the vasculature, either by influencing vessel structure and perfusion or by altering endothelial secretion of supportive angiocrine factors. These findings lay the ground for a detailed analysis of the mechanisms by which senescent tumor endothelial cells affect tumor growth and progression.