Hypoxia-induced dedifferentiation of tumor cells--a mechanism behind heterogeneity and aggressiveness of solid tumors.

Histopathological examination of solid tumors frequently reveals pronounced tumor cell heterogeneity with regards to cell organization, cell morphology, cell size, nuclei morphology, etc. Analyses of gene expression patterns by immunohistochemistry or in situ hybridization techniques further strengthen the actual presence of phenotypic heterogeneity, often demonstrating substantial diversity within a given tumor. The molecular mechanisms underlying the phenotypic heterogeneity are very complex with genetic, epigenetic and environmental components. Hypoxia, shortage in oxygen, greatly influences cellular phenotypes by altering the expression of specific genes, and is an important contributor to intra- and inter-tumor cell diversity as revealed by the pronounced but non-uniform expression of hypoxia-driven genes in solid tumors (reviewed in [Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer 2003;3:721-32; Harris AL. Hypoxia--a key regulatory factor in tumour growth. Nat Rev Cancer 2002;2:38-47.]). The oxygen pressure in solid tumors is generally lower than in the surrounding non-malignant tissues, and tumors exhibiting extensive hypoxia have been shown to be more aggressive than corresponding tumors that are better oxygenized [Vaupel P. Oxygen transport in tumors: characteristics and clinical implications. Adv Exp Med Biol 1996;388:341-51; Vaupel P, Thews O, Hoeckel M. Treatment resistance of solid tumors: role of hypoxia and anemia. Med Oncol 2001;18:243-59.]. We recently observed that hypoxic neuroblastoma cells and breast cancer cells lose their differentiated gene expression patterns and develop stem cell-like phenotypes [Jögi A, Øra I, Nilsson H, Lindeheim A, Makino Y, Poellinger L, et al. Hypoxia alters gene expression in human neuroblastoma cells toward an immature and neural crest-like phenotype. Proc Natl Acad Sci USA 2002;99:7021-6; Helczynska K, Kronblad A, Jögi A, Nilsson E, Beckman S, Landberg G, et al. Hypoxia promotes a dedifferentiated phenotype in ductal breast carcinoma in situ. Cancer Res 2003;63:1441-4.]. As low stage of differentiation in neuroblastoma and in breast cancer is linked to poor prognosis, hypoxia-induced dedifferentiation will not only contribute to tumor heterogeneity but could also be one mechanism behind increased aggressiveness of hypoxic tumors. The effect(s) of hypoxia on tumor cell differentiation status is the focus of this review.