Endogenous markers of hypoxia/anaerobic metabolism and anemia in primary colorectal cancer.
Anemia has been implicated in the decreased oxygen tension noted within the tumor environment. In a series of 79 colorectal adenocarcinomas we investigated the role of anemia in activating molecular pathways regulated by hypoxia. Preoperative Hb levels were correlated with the immunohistochemical expression of HIF1alpha and HIF2alpha, LDH5, GLUT1, VEGF, DEC1 and BNIP3, and with angiogenesis and the cancer cell proliferation index. Upregulation of HIF1alpha and HIF2alpha proteins, found in 43% and 44.3% of cases, respectively, was not related to anemia (Hb < 10 g%). This is in agreement with other studies suggesting that HIF activation occurs for various reasons, such as poor or irregular vascularity, or oncogene activation. Nevertheless, low Hb levels (<10 g%) were linked to activated anaerobic metabolism (LDH5 overexpression) in a subset of tumors not expressing HIF1alpha (P < 0.01). Overexpression of HIFs, whether linked to anemia or not, was associated with a number of factors related to tumor aggressiveness (assessed as local invasion and nodal metastasis), anaerobic metabolism and intratumoral acidosis (LDH5, GLUT1; increased glucose metabolism to lactate), activation of genes related to necrosis (BNIP3) and angiogenesis (VEGF). Expression of BNIP3 emerged as the strongest independent factor related to transmural invasion and metastasis to lymph nodes. Identification of specific patterns of the hypoxia molecular cascade activated in cancer cells might help in developing specific therapeutic policies.
Koukourakis
Michael I
MI
Department of Radiotherapy/Oncology, Democritus University of Thrace, Alexandroupolis, Greece. targ@her.forthnet.gr
Giatromanolaki
Alexandra
A
Polychronidis
Alexandros
A
Simopoulos
Costantinos
C
Gatter
Kevin C
KC
Harris
Adrian L
AL
Sivridis
Efthimios
E
D000230:Adenocarcinoma / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D000693:Anaerobiosis; D000740:Anemia / Q000175:diagnosis* / Q000209:etiology / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000032:analysis* / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000032:analysis / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D051272:Glucose Transporter Type 1 / Q000032:analysis / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000175:diagnosis* / Q000209:etiology / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis* / Q000378:metabolism; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000032:analysis / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000032:analysis / Q000378:metabolism; D000080864:Lactate Dehydrogenase 5; D008565:Membrane Proteins / Q000032:analysis / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism; D015513:Oncogene Proteins / Q000032:analysis / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000032:analysis / Q000378:metabolism; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D051272:Glucose Transporter Type 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007527:Isoenzymes; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5; D008565:Membrane Proteins; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A; D000099162:Endothelial PAS Domain-Containing Protein 1; C090121:BNIP3 protein, human; C403671:DELEC1 protein, human; C497442:HIF1A protein, human; C115081:MCTS1 protein, human; C495677:SLC2A1 protein, human