Hypoxia-inducible factor-1α expression predicts the response to 5-fluorouracil-based adjuvant chemotherapy in advanced gastric cancer

Abstract

Abstract. Hypoxia frequently occurs in various solid tumors, thereby accelerating cancer progression and treatment resistance. Hypoxia-inducible factor-1· (HIF-1·) plays a central role in tumor hypoxia by up-regulating the gene expression related to angiogenesis, cancer invasion and anti-apoptosis. The present study immunohistochemically investigated HIF-1· expression in 63 gastric cancer specimens. Those specimens were obtained from 44 patients that received 5-FU chemotherapy post-operatively whereas the remaining 19 patients did not. The immunostaining pattern of HIF-1· was classified into 3 patterns: diffuse-positive within the tumor (DP), positive at the invasive front of the tumor (FP) and negative (N). Thirty-six of 63 (57.1%) patients exhibited DP, 24 (38.1%) revealed FP and the remaining 3 (4.8%) patients were judged as N. The HIF-1· expression pattern grouped into DP and FP/N correlated with the clinicopathological factors and survival. As a result, the HIF-1· expression did not show a significant correlation with the clinicopathological factors, such as the depth of invasion, lymph node metastasis and tumor stage, nor patient survival in the 63 patients. However, in the 44 patients that underwent chemotherapy, patients with the FP/N pattern showed longer survival than those with the DP pattern. On the other hand, no significant difference in survival was found between the 2 patterns among 19 patients without the chemotherapy. These results indicated that the diffuse expression of HIF-1· in gastric tumors might lead to drug resistance against adjuvant chemotherapy using 5-FU. In conclusion, the assessment of the HIF-1· expression in the resected tissues might predict the drug response to adjuvant 5-FU chemotherapy in advanced gastric cancer patients.

Adapting and Surviving: Intra and Extra-Cellular Remodeling in Drug-Resistant Gastric Cancer Cells

“…Even if HIF-1α-dependent molecular mechanisms in chemo-sensitivity have been only partially elucidated, suppression of p53 and activation of nuclear factor κB (NF-κB) seem to play a key role in hypoxia-related 5-fluorouracil (5-FU) and cisplatin (CDDP) sensitivity in human GC cells [49]. It has been reported that HIF-1α induces drug resistance to adjuvant chemotherapy with 5-FU in advanced GC patients [50]. Moreover, the overexpression of HIF-1α leads to hypoxia-induced drug resistance by increasing the expression of Bcl-2, P-glycoprotein (P-gp) and MRP1, and reducing the expression of Bax [51].…”

Clinical progress of anti-angiogenic targeted therapy and combination therapy for gastric cancer

“…Chemotherapy combined with sorafenib can effectively reduce serum HIF-1α and VEGF levels in patients with GC to improve their 1-year survival rate and prognosis ( 116 ). Diffuse expression of HIF-1α in gastric tumors may lead to resistance to adjuvant chemotherapy with 5-FU ( 163 ). Local amplification of associated genes ARID1A, PIK3CA, and P53, as well as HMGA2 and MET, also benefited from sorafenib treatment ( 112 ).…”