Hypoxia-inducible factor-1α expression and gemcitabine chemotherapy for pancreatic cancer

Abstract

Abstract. The normal pancreas has an abundant blood flow, in contrast to pancreatic cancer, which is a hypovascular tumor. During hypoxia under a hypovascular environment, the transcription factor hypoxia-inducible factor-1α (HIF-1α) is activated. High HIF-1α expression reduces sensitivity to gemcitabine (GEM) which is used as a treatment for pancreatic cancer. The objective of this study was to clarify HIF-1α expression in pancreatic cancer and the association of its effects to GEM treatment. We used the human pancreatic ductal carcinoma cell lines AsPC-1 and BxPC-3 to evaluate cell proliferation, HIF-1α protein expression and sensitivity to GEM in a hypoxic environment of 1% O 2 in 48 pancreatic cancer patients who received adjuvant GEM treatment after pancreatectomy. We divided the patients according to HIF-1α expression and the presence of single nucleotide polymorphisms, and we based our evaluation on the adverse events associated with GEM chemotherapy and patient outcome. The hypoxic environment promoted cell proliferation, induced HIF-1α expression and increased GEM resistance, especially in AsPC-1 cells, which included a mutant homozygote for HIF-1α(C1772T). There were no significant differences between the HIF-1α(-) and HIF-1α(+) groups in either adverse events or patient outcomes. HIF-1α enhanced neo-microvascularity in a hypoxic environment and increased drug resistance. The period until recurrence was shorter in the patients with a strong HIF-1α expression, than that in those with a weak HIF-1α expression.

Feasibility and repeatability of PET with the hypoxia tracer [18F]HX4 in oesophageal and pancreatic cancer

“…The pancreatic tumour microenvironment is characterized by hypoxia, resulting from an abundance of stromal tissue and reduced vascularization [8][9][10]. Several studies have shown the relation of tumour hypoxia with adverse outcome in both oesophageal [11] and pancreatic cancer [12]. Hypoxia driven cell preserving pathways are associated with a more aggressive and metastatic tumour phenotype as well as resistance to chemotherapy and radiation [13][14][15][16].…”

Hypoxia regulates ABCG2activity through the activivation of ERK1/2/HIF-1α and contributes to chemoresistance in pancreatic cancer cells

“…6 HIF-1a overexpression has been detected in several solid tumors and is correlated with progression of a variety of cancers, including ovarian carcinoma, cervical carcinoma, oropharyngeal squamous cell carcinoma, non-small-cell lung cancer and pancreatic cancer. [7][8][9][10][11] It has been demonstrated that HIF-1a affects the regulation of cancer cell proliferation, angiogenesis, apoptosis and chemotherapeutic resistance during tumor development. 12 Although HIF-1a has been reported to promote cell survival and may be associated with drug resistance in pancreatic cancer, 11,13 the underlying mechanism still remains to be elucidated.…”

“…[7][8][9][10][11] It has been demonstrated that HIF-1a affects the regulation of cancer cell proliferation, angiogenesis, apoptosis and chemotherapeutic resistance during tumor development. 12 Although HIF-1a has been reported to promote cell survival and may be associated with drug resistance in pancreatic cancer, 11,13 the underlying mechanism still remains to be elucidated. Nuclear accumulation is an important process of HIF-1a activity.…”

Scientific rationale for integrative and personalised strategies for pancreatic ductal adenocarcinoma management

“…Increased expression of miR-21 and decreased expression of miR-200 contribute to chemoresistance to gemcitabine as well as increase aggressiveness of cancer cells [180]. Additionally, loss of p53 function, increased expression of anti-apoptotic protein (Bcl family protein), NF-κB and hypoxia-inducible factor 1-alpha and higher activation of SRC kinase, EGFR, STAT3, PI3K/AKT, Notch and MAPK pathway during pancreatic carcinogenesis confers resistance to gemcitabine [178][179][180][181][182][183][184]. Similarly, activation of molecular cascades including antiapoptotic, SRC kinase and EGFR/AKT provides survival benefits to PDAC cells during the course of prolonged 5-FU treatment [180,186].…”