Lung cancer is the leading cause of
cancer-related deaths worldwide, and treatments for
lung cancer have a high failure rate. Anti-angiogenic
therapy is also often ineffective because of refractory disease.
Endostatin (ES) is one of the most widely-used
anti-angiogenic drugs for
lung cancer in China, and resistance to it is a barrier that needs to be resolved. It has been shown that myeloid-derived suppressor cells (MDSCs) are involved in resistance to ES. Whether other cells and/or cell factors in the tumor microenvironment that have been shown to be related to resistance to other anti-
cancer drugs are also involved in ES resistance is unknown.
RESULTS: In this study, we showed that after continuously treatment with ES for 12 days, volumes of A549
transplantation tumors of mice reached the sizes of
tumors which were borne by mice that were treated with
normal saline and this meant that resistance to ES appeared. Cancer stem cells (CSCs), which have been widely accepted as one of reasons responsible for resistance to many anti-
tumor drugs were also being discovered increased proportionally in A549
transplantation tumors after ES treatment for 12 days. During further exploration of reasons for this increase, we discovered that after ES treatment, microvessel density and
vascular endothelial growth factor level was decreased in
tumors, whereas
transforming growth factor (TGF)-β1 level was elevated, and MDSCs, one of the sources of TGF-β1, were also increased. We speculate that
hypoxia and TGF-β1 are responsible for the increased CSC number in A549
transplantation tumors. By using
cobalt chloride to mimic
hypoxia and human recombinant TGF-β1 in vitro, we found that
hypoxia and TGF-β1can indeed enhance the stemness of A549 cells. In addition, the inductive effect of
hypoxia is stronger than TGF-β1, and the combination of both is stronger than either alone, which is first report of such a finding, to our knowledge.
CONCLUSIONS: Increased TGF-β1 and strengthened
hypoxia in A549
transplantation tumors, as a result of ES
therapy, cooperatively increase proportion of CSCs that are involved in ES resistance which was revealed by failure of
tumor volume repression after continuously treatment with ES for 12 days.