Researchers at Hokkaido University and collaborators say they have identified how inflammatory changes in tumors caused by chemotherapy trigger blood vessel anomalies leading to drug-resistance, resulting in poor prognosis of cancer patients. Through experiments with mice, the team also found that the combined usage of an inhibitor and anticancer drug makes chemotherapy more effective.

The scientists report their work Chemotherapy-Induced IL8 Upregulates MDR1/ABCB1 in Tumor Blood Vessels and Results in Unfavorable Outcome” in Cancer Research.

“Tumor endothelial cells (TEC) lining tumor blood vessels actively contribute to tumor progression and metastasis. In addition to tumor cells, TEC may develop drug resistance during cancer treatment, allowing the tumor cells to survive chemotherapy and metastasize. We previously reported that TECs resist paclitaxel treatment via upregulation of ABCB1. However, whether TEC phenotypes are altered by anticancer drugs remains to be clarified,” write the investigators.

“Here, we show that ABCB1 expression increases after chemotherapy in urothelial carcinoma cases. The ratio of ABCB1-positive TEC before and after first-line chemotherapy in urothelial carcinoma tissues (n = 66) was analyzed by ABCB1 and CD31 immunostaining. In 42 cases (64%), this ratio increased after first-line chemotherapy. Chemotherapy elevated ABCB1 expression in endothelial cells by increasing tumor IL8 secretion. In clinical cases, ABCB1 expression in TEC correlated with IL8 expression in tumor cells after first-line chemotherapy, leading to poor prognosis. In vivo, the ABCB1 inhibitor combined with paclitaxel reduced tumor growth and metastasis compared with paclitaxel alone.”

ABCB1-Positive Blood Vessels After Chemotherapy
ABCB1-positive blood vessels (brown) after first-line chemotherapy in human urothelial carcinoma. Red and white arrowheads indicate ABCB1-positive and negative blood vessels, respectively. (Kikuchi H., et al., Cancer Research, June 15, 2020) [Kikuchi H., et al., Cancer Research, June 15, 2020]
“Chemotherapy is suggested to cause inflammatory changes in tumors, inducing ABCB1 expression in TEC and conferring drug resistance. Overall, these findings indicate that TEC can survive during chemotherapy and provide a gateway for cancer metastasis. Targeting ABCB1 in TEC represents a novel strategy to overcome cancer drug resistance.

“These findings show that inhibition of ABCB1 in tumor endothelial cells may improve clinical outcome, where ABCB1 expression contributes to drug resistance and metastasis following first-line chemotherapy.”

Chemotherapy is often chosen for treating inoperable cancers, such as locally advanced and metastasis cases. It is, therefore, essential to unravel drug-resistance in this treatment, which has been a major factor in making cancer malignant and causing metastasis.

Tumor blood vessels play a key role in cancer progression because they carry nutrients and oxygen to tumors and serve as pathways for metastasis. It had been generally believed that tumor endothelial cells (TEC) lining tumor blood vessels did not acquire drug-resistance. However, several years ago, the group’s mice experiments showed TEC can obtain various anomalies, suggesting blood vessels, as well as cancer cells, can contribute to making tumors drug-resistant.

ABCB1 expression was increased in tumor blood vessels of more than 60 percent of patients who received chemotherapy. (Kikuchi H., et al., Cancer Research, June 15, 2020) [Kikuchi H., et al., Cancer Research, June 15, 2020]
For example, the team demonstrated for the first time that TEC in blood vessels resist paclitaxel , which is used for second-line treatment of urothelial cancer, due to the expression of ABCB1 which pumps out the drug from blood vessels. However, much remains unknown about how human blood vessels are involved in cancer acquiring drug-resistance.

To help unravel this mystery, the scientists first analyzed tumor tissue samples from urothelial cancer patients before and after they underwent first-line chemotherapy. They found ABCB1 expression was increased in TEC in blood vessels of more than 60 percent of patients who received chemotherapy, and that their prognoses were poorer than patients whose ABCB1 expression remained the same after the treatment.

In addition, they analyzed TEC in blood vessels and bladder cancer cells to study how chemotherapy affects ABCB1 expression. The results showed that the increased secretion of interleukin-8 (IL-8) in cancer cells after chemotherapy caused inflammatory changes, increasing the ABCB1 expression in TEC.

In another experiment, mice with urothelial cancer administered with the ABCB1 inhibitor together with paclitaxel showed suppressed formation of new blood vessels and thus metastasis to the lung.

“Our study provides evidence, for the first time in humans, that inflammatory changes in tumors can cause drug resistance in cancer blood vessels,” says Kyoko Hida, DDSc, PhD,  of Hokkaido University who led the group. “These findings could help devise new treatment strategies, such as the development of inhibitors targeting ABCB1 and IL-8, to suppress drug resistance and improve prognosis.”

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