ReviewHypoxia-induced dedifferentiation of tumor cells – A mechanism behind heterogeneity and aggressiveness of solid tumors
Section snippets
Intra-tumoral phenotypic heterogeneity
It is generally believed that tumor development occurs in a stepwise manner, with a progressive accumulation of genetic and epigenetic changes. The driving force in this process is the selection of cells with a growth and/or survival advantage, leading to successive clonal expansion of tumor cell populations (Fig. 1). It is the accumulated, combined effects of these changes that lead to a full tumorigenic conversion. In some tumors, such as colorectal cancer, detailed molecular characterization
Cellular adaptation to hypoxia
As discussed in more detail by others in this issue, cells can adapt to low oxygen levels by changing their gene expression patterns through a transcriptional response pathway mediated by the hypoxia inducible factor (HIF)-1 and the related transcription factors HIF-2 and HIF-3. The α-subunits of these heterodimeric factors become stabilized and activated under hypoxic conditions, and form complexes with the constitutively expressed transcription factor ARNT/HIF-1β [1], [2], [13]. At normoxia,
Neuroblastoma derivation and development of the sympathetic nervous system
Neuroblastoma is a tumor of the early childhood. It has been recognized and extensively studied much due to the high frequency of spontaneous neuroblastoma cell maturation converting the tumor into a benign form, ganglioneuroma [16]. Primary tumor localization and a detailed characterization of marker gene expression of developing sympathetic nervous system (SNS) cell types in comparison to the expression of these genes in neuroblastoma tumors, reveal that neuroblastomas are derived from SNS
Hypoxia regulates lineage specifying basic helix-loop-helix (bHLH) transcription factors
The sequential molecular steps involved on the conversion of migrating neural crest cells to sympathetic precursors and finally to non-migrating sympathetic neuroblasts, or SNS chromaffin precursor cells, are far from known. However, gene elimination and overexpression approaches have identified several genes important to these processes, including those coding for the bHLH transcription factors HASH-1, dHAND and MYCN. Our initial observations that these genes were downregulated in hypoxic
Hypoxia promotes an immature phenotype in breast carcinoma in situ
In neuroblastoma, there is a well-established association between low stage of differentiation and poor clinical outcome, suggesting that dedifferentiation of neuroblastoma cells caused by hypoxia could be one mechanisms behind the progression of a tumor from being treatment responsive to become refractive. Having disclosed that neuroblastoma cells lose differentiation characteristics during hypoxic growth, the obvious question was whether hypoxia had similar effects on other tumor forms. We
Poor tissue oxygenation – a tumor-promoting condition?
Data presented so far have focused on a dedifferentiating effect on tumor cells of low oxygen, a consequence of hypoxia that is in keeping with the documented more aggressive phenotype of hypoxic tumors [3], [4]. The generality of the dedifferentiating effect of hypoxia on tumor cells remains however to be investigated since so far only two tumor forms, neuroblastoma and breast cancer have been studies in any detail. However, hypoxic LnCap prostate carcinoma cells loose their PSA and androgen
Concluding remarks
With the disclosure of the negative effects of hypoxia on tumor growth and behavior, and HIFs as the main molecular triggers of these effects, HIF-1α has been identified and is explored as a molecular target for treatment of aggressive tumors (reviewed in [1]). As the hypoxic phenotype is principally restricted to tumors, genes selectively expressed due to poor oxygenation can be considered to be tumor-specific. Thus, one obvious advantage of targeting the HIF-1α protein is its tumor specific
Acknowledgements
This work was supported by grants from the Swedish Cancer Society, Children's Cancer Foundation of Sweden, HKH Kronprinsessan Lovisas förening för barnasjukvård, Hans von Kantzows stiftelse, Ollie och Elof Ericssons stiftelse and the research funds of Malmö University Hospital. H.A. and E.F. are supported by grants from the Children's Cancer Foundation of Sweden and the KK-foundation, respectively.
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