Cancer cells require nutrients and oxygen to support their robust growth. Angiogenesis, the formation of new blood vessels from pre-existing vasculature, addresses those needs. Therefore, antiangiogenic treatment was considered a promising therapeutic strategy [
1,
2]. Vascular endothelial growth factor (VEGF) plays a central role in this process through the activation of its receptor tyrosine kinases (RTKs), including VEGFR1, VEGFR2, and VEGFR3, on endothelial cells (ECs) [
3,
4]. Sunitinib is a multitarget RTK inhibitor of VEGF receptors that targets VEGFR1, VEGFR2, and VEGFR3 as well as platelet-derived growth factor receptor (PDGFR), stem cell growth factor receptor, and FMS-like tyrosine kinase 3 [
5‐
7]. Sunitinib has been approved for patients with advanced renal cell carcinoma, pancreatic neuroendocrine tumors, and gastrointestinal stromal tumors [
8]. However, it was not as successful in certain cancer types, particularly metastatic breast cancer (MBC). Patients with MBC exhibited inferior progression-free survival (PFS) and overall survival (OS) when treated with chemotherapy plus sunitinib compared with patients treated with monochemotherapy [
9‐
11]. In a phase II randomized trial, sunitinib treatment as a consolidation therapy after an objective response to taxane resulted in a shorter median PFS versus no treatment at all [
12], and studies based on mouse models found that sunitinib could even accelerate the metastasis of breast cancer [
6,
13]. A meta-analysis comprising 6 randomized controlled trials showed that sunitinib, either alone or in combination with chemotherapy, has no clinical benefit for patients with MBC [
14]. Studies have attempted to investigate this “sunitinib resistance,” but the molecular basis underlying the ineffectiveness of sunitinib treatment in MBC is still lacking.
ECs not only play prominent roles in vasculature formation but also are critical components of the tumor microenvironment and the metastatic niche [
15]. Because sunitinib targets almost all VEGF receptors and PDGFR expressed on the EC surface, we speculated that sunitinib might either attack the ECs directly or affect their normal functions both in the tumor vasculature and in the normal vasculature. Many anticancer drugs affect not only tumor cells (TCs) but also normal cells. In addition to their role in direct causing cell damage, anticancer drugs also induce cell senescence in the tumor microenvironment, including cancer cells [
16] and noncancerous cells, such as fibroblasts, infiltrating immune cells, and ECs [
17,
18]. Although drug-induced senescence could stimulate immunosurveillance, it could also promote the growth and aggressiveness of cancer cells by inducing the production of inflammatory cytokines, chemokines, and growth factors [
19]. EC senescence was recently reported to facilitate metastasis [
20]. Based on these studies, we hypothesized that sunitinib resistance, or a sunitinib-associated inferior survival benefit in MBC, may be due to sunitinib-induced EC injury or senescence.
Herein, we use 4T1 murine breast cancer cells as the main tool to study the effect of sunitinib on an MBC tumor model. We chose the 4T1 cell line because it produces a highly metastatic solid tumor that can spontaneously metastasize to the lung, which closely mimics highly metastatic human breast cancer [
21,
22]. Our data suggest that sunitinib does not cause direct EC damage but induces a senescence-like EC phenotype. The presence of senescent ECs increased inflammatory chemokine secretion and VCAM1 expression, which attracted tumor cells (TCs) of MBC to ECs and facilitated the TC/EC interaction. Meanwhile, the expression of the key junction molecule VE-cadherin was reduced in the senescent ECs, resulting in the opening of EC junctions, which favors TC transmigration to the endothelial barrier. In addition, senescent ECs recruited cancer-associated inflammatory myeloid cells, including neutrophils and macrophages, which contributed to the formation of a “premetastatic niche”-like microenvironment. These molecular and environmental changes ultimately led to an increase in lung metastasis. Our study provides a possible explanation for the phenomenon that sunitinib has no clinical benefit in patients with MBC and improves our understanding of the mechanism underlying the observed drug resistance to antiangiogenic therapies.