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Characterization of hypoxic tumor regions in a syngeneic rat hepatoma model
Author(s) -
Khan Zahida,
Bowen William C.,
Stolz Donna B.,
Michalopoulos George K.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1091
Subject(s) - hypoxia (environmental) , angiogenesis , hepatocellular carcinoma , hypoxia inducible factors , cancer research , metastasis , pathology , in vivo , hif1a , hypervascularity , tumor hypoxia , immunohistochemistry , liver cancer , biology , medicine , cancer , chemistry , radiation therapy , gene , biochemistry , microbiology and biotechnology , organic chemistry , oxygen
Background Hepatocellular carcinoma (HCC) is the 5 th most common solid tumor worldwide and 4 th leading cause of cancer death. HCC is highly vascular with a strong propensity for invasion. Hypoxia‐inducible factor (HIF), a potent inducer of angiogenesis, is an ideal target for anti‐angiogenic strategies. HIF transcription factors upregulate hypoxia‐responsive genes and are post‐translationally controlled by O 2 ‐dependent HIF prolyl 4‐hydroxylases (PHD). These novel enzymes are highly expressed in liver, a unique organ due to its physiologic O 2 gradient. Hypothesis Dysregulation of PHDs leads to HIF over‐expression and hypervascularity in HCC. Here we describe a syngeneic rat hepatoma model to study hypoxic regions of tumors.Methods JM1 (↑invasive) or JM2 (↓aggressive) rat hepatoma cells were transplanted into livers of Fisher 344 rats. After 2–4wk of syngeneic engraftment, rats were injected with Hypoxyprobe ™ (pimonidazole) hypoxia marker 1hr before harvesting livers. Hypoxia markers were analyzed on tumor and normal adjacent liver (NAL) serial sections. Results JM1 hepatomas, unlike JM2, progressed from single nodules to metastases in 2–4wk. Hypoxyprobe ™ consistently identified tumor hypoxia and compressed NAL in hepatomas. Nuclear HIF‐1α co‐localized to hypoxic regions. Surprisingly, tumors had ↑PHD1–3 with distinct subcellular localization. Conclusion Tissue hypoxia in hepatomas clearly disrupts the liver's physiologic O 2 gradient. Preliminary results show differential expression of HIFs and PHDs in NAL vs. tumors. Our syngeneic hepatoma model provides a practical method of tumor cell engraftment and metastasis without immunosuppression. This is a functional in vivo approach to test potential anti‐angiogenic regulators of the HIF pathway and to advance our knowledge of HCC pathophysiology. (PHS1T32EB001026/CA35373/CA103958)