Abstract LB-376: Hypoxia-inducible factor-1 alpha is an unfavorable determinant of relapse in gastric cancer patients who underwent curative surgery followed by adjuvant 5-fluorouracil chemotherapy
Authors: Nakamura Jun , Kitajima Yoshihiko , Kai Keita , Hashiguchi Kazuyoshi , Hiraki Masatsugu , Noshiro Hirokazu , Miyazaki Kohji 
Published: February 2011

Background: Among several chemotherapeutic agents, 5-Fluorouracil (5-FU) has been widely used as a key drug in adjuvant chemotherapy for gastric cancer. However, no reliable marker, which predicts the response to 5-FU in an adjuvant setting, has been identified. Hypoxia-induced drug resistance, via up-regulation of hypoxia-inducible factor (HIF) -1α, is a major obstacle in the development of effective cancer therapy. Despite the numerous investigations, few clinical studies have so far assessed the relationship between the HIF-1α expression and the chemo-resistance of gastric cancer patients in an adjuvant setting.

Objective: To determine whether the expression of HIF-1α predicts the relapse of gastric cancer patients who underwent curative surgery followed by adjuvant 5-FU chemotherapy.

Materials and Methods: Two HIF-1α knockdown gastric cancer cell lines were established in order to clarify the role of HIF-1α in chemo-resistance against 5-FU. The sensitivity to 5-FU was evaluated by MTT assay, and compared between HIF-1α knockdown cells and control scrambled cells. 5-FU-induced apoptosis was assessed by flow cytometry and the DNA ladder. Furthermore, HIF-1α knockdown xenograft models of nude mice were established to confirm the role of HIF-1α in 5-FU chemo-resistance in vivo. A total of 91 patients with locally advanced gastric cancer who underwent a curative resection were enrolled. Sixty-four of 91 patients received 5-FU based adjuvant chemotherapy after curative surgery. The expression of HIF-1α was immunohistochemically assessed, and correlated with the patient outcome.

Results: The inhibition of HIF-1α improved the sensitivity to 5-FU in gastric cancer cell lines, and promoted 5-FU-induced apoptosis in vitro and in vivo. The effect of HIF-1α knockdown on 5-FU-induced apoptosis was more distinctly observed in xenograft tumor than in cell culture. In immunohistochemical analysis, HIF-1α expression was associated with the significantly shorter relapse-free survival and disease-specific survival in all gastric cancer patients (p = 0.045, 0.025), and in the 64 patients in the adjuvant group (p = 0.026, 0.014), but not in the 27 in the surgery group. Multivariate analysis showed that HIF-1α was an independent risk factor for relapse in 64 patients in the adjuvant group (p = 0.029).

Conclusions: The current study demonstrated, for the first time, that HIF-1α expression is an independent risk factor for relapse in advanced gastric cancer patients who underwent curative surgery followed by adjuvant 5-FU chemotherapy. A favorable effect of 5-FU might therefore be expected in patients that do not express HIF-1α, whereas, other types of chemotherapy or additional treatments, such as HIF-1α inhibitors, should be considered in patients that do express HIF-1α.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-376.