Abstract
BackgroundIt is widely accepted that the oxygen level in tumor tissue is significantly lower than the adjacent normal tissue, thus termed hypoxia. Intratumoral hypoxia represents a major driving force in cancer progression, recurrence, metastasis, and decreased survival. Though multiple gene signatures reflect the complex cellular response to hypoxia have been established in several cancer types such as head and neck, breast, and lung cancers, the hypoxic panorama in colorectal cancer (CRC) remains poorly understood.MethodsA hypoxic signature constituted by a total of 356 genes, including canonical hypoxia-responsive ADM, ANGPTL4, CA9, and VEGFA, was established based on systemic literature search. A total of 1,730 CRC samples across four independent cohorts were used for nonnegative matrix factorization clustering and subtyping. Prognosis, molecular signatures, pathways, and tumor-infiltrating lymphocytes were compared between the subtypes.ResultsCRCs mainly fell into two subgroups, one indicated as hypoxia and the other one designated as normoxia. Hypoxia was correlated with poor outcomes in CRC and will increase the risk of a subset of stage II patients to the level of normoxic stage III. Additionally, hypoxia was closely associated with activation of RAS signaling pathway independent of KRAS mutation. More M2 macrophage infiltration was another hypoxic marker indicated that subsets of patients with high M2 macrophages may benefit from macrophage-targeting therapy.ConclusionsThese findings will facilitate the development of a hypoxia-oriented therapy strategy to enhance the treatment effect in the near future.
Highlights
Tumor hypoxia is correlated with advanced progression, treatment resistance and poor clinical outcomes [1, 2]
To build a robust hypoxia signature, we collected a list of wellannotated gene expression signatures across different cancer types, including the well-known pancancer hypoxia 15-gene [5], 26-gene hypoxia signature in laryngeal cancer [6], 24-gene hypoxia signature in high-risk bladder cancer [7], 20-gene that showed the greatest fold induction following hypoxic exposure in MCF7 cells [8], 28gene hypoxia-related prognostic signature for localized prostate cancer [9], hypoxia gene expression classifier in head and neck cancer [4, 10], 27-gene that was found as hypoxia induced, pH unaffected in human squamous cell carcinomas [11], nine-gene derived from Caco-2 colorectal cancer (CRC) cells in response to hypoxia [12], and 200-gene under hypoxia hallmark in Molecular Signatures Database (MSigDB) [13]
To validate the two subgroups identified in The Cancer Genome Atlas (TCGA) cohort, we examined three other datasets GSE39582 (French Ligue Nationale Contre le Cancer), GSE17538 (61 from Vanderbilt Medical Center and 177 patients from the Moffitt Cancer Center), and GSE14333
Summary
Tumor hypoxia is correlated with advanced progression, treatment resistance and poor clinical outcomes [1, 2]. It is widely accepted that the oxygen level in hypoxic tumor tissue is significantly lower than the oxygenation of the respective normal tissues and on average it is between 1%–2% O2 and below [3]. Intratumoral hypoxia is a well established resistance factor for radiotherapy and is Hypoxia in CRC increasingly recognized as promoting resistance to systemic cancer therapies. Hypoxia promotes a more aggressive and resistant cancer phenotype, primarily mediated by hypoxia-inducible factor 1 (HIF-1), a transcription factor that is stable only in lowoxygen condition, which leads to cell cycle arrest, angiogenesis, and accelerated glycolysis [3]. It is widely accepted that the oxygen level in tumor tissue is significantly lower than the adjacent normal tissue, termed hypoxia. Though multiple gene signatures reflect the complex cellular response to hypoxia have been established in several cancer types such as head and neck, breast, and lung cancers, the hypoxic panorama in colorectal cancer (CRC) remains poorly understood
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