Research Papers:

Capecitabine reverses tumor escape from anti-VEGF through the eliminating CD11bhigh/Gr1high myeloid cells

Toshiki Iwai, Yui Harada, Hiroshi Saeki, Eiji Oki, Yoshihiko Maehara and Yoshikazu Yonemitsu _

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Oncotarget. 2018; 9:17620-17630. https://doi.org/10.18632/oncotarget.24811

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Toshiki Iwai1,2,3, Yui Harada2, Hiroshi Saeki1, Eiji Oki1, Yoshihiko Maehara1 and Yoshikazu Yonemitsu2

1Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

2R&D Laboratory for Innovative Biotherapeutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan

3Product Research Department, Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd., Kanagawa, Japan

Correspondence to:

Yoshikazu Yonemitsu, email: [email protected]

Keywords: anti-VEGF; capecitabine; myeloid-derived suppressor cells; tumor angiogenesis; pyrimidine nucleotide phosphorylases

Received: October 31, 2017     Accepted: February 25, 2018     Published: April 03, 2018


The anti-VEGF humanized antibody bevacizumab suppresses various malignancies, but tumors can acquire drug resistance. Preclinical studies suggest myeloid-derived suppressor cells (MDSCs) may be associated with tumor refractoriness to anti-VEGF treatment. Here we report a novel mechanism of tumor escape from anti-VEGF therapy. Anti-VEGF treatment enhanced intratumoral recruitment of CD11bhigh/Gr-1high polymorphonuclear (PMN)-MDSCs in anti-VEGF-resistant Lewis lung carcinoma tumors. This effect was diminished by the anticancer agent capecitabine, a pro-drug converted to 5-fluorouracil, but not by 5-fluorouracil itself. This process was mediated by enhanced intratumoral granulocyte-colony stimulating factor expression, as previously demonstrated. However, neither interleukin-17 nor Bv8, which were previously identified as key contributors to anti-VEGF resistance, was involved in this model. Capecitabine eliminated PyNPase-expressing MDSCs from both tumors and peripheral blood. Capecitabine treatment also reversed inhibition of both antitumor angiogenesis and tumor growth under anti-VEGF antibody treatment, and this effect partially inhibited in tumors implanted in mice deficient in both PyNPases. These results indicate that intratumoral granulocyte-colony stimulating factor expression and CD11bhigh/Gr-1high PMN-MDSC recruitment underlie tumor resistance to anti-VEGF therapy, and suggest PyNPases are potentially useful targets during anti-angiogenic therapy.

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