Open AccessEndogenous markers of hypoxia/anaerobic metabolism and anemia in primary colorectal cancer
Author(s) -
Koukourakis Michael I.,
Giatromanolaki Alexandra,
Polychronidis Alexandros,
Simopoulos Costantinos,
Gatter Kevin C.,
Harris Adrian L.,
Sivridis Efthimios
Publication year - 2006
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2006.00220.x
Subject(s) - angiogenesis , cancer research , metastasis , hypoxia (environmental) , biology , glut1 , hypoxia inducible factors , colorectal cancer , anemia , hif1a , medicine , cancer , pathology , endocrinology , glucose transporter , chemistry , biochemistry , organic chemistry , oxygen , gene , insulin
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 HIF1α and HIF2α, LDH5, GLUT1, VEGF, DEC1 and BNIP3, and with angiogenesis and the cancer cell proliferation index. Upregulation of HIF1α and HIF2α 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 HIF1α ( 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. ( Cancer Sci 2006; 97: 582–588)