Hypoxia enhances colon cancer migration and invasion through promotion of epithelial-mesenchymal transition

Hongo, Kumiko; Tsuno, Nelson H.; Kawai, Kazushige; Sasaki, Kazuhito; Kaneko, Manabu; Hiyoshi, Masaya; Murono, Koji; Tada, Noriko; Nirei, Takako; Sunami, Eiji; Takahashi, Koki; Nagawa, Hirokazu; Kitayama, Joji; Watanabe, Toshiaki

doi:10.1016/j.jss.2012.08.034

Cited by 47 publications

(38 citation statements)

References 37 publications

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“…The oxygen concentration decreases along the GI tract, and this fact could explain why CEACAM6 is expressed at basal levels in colonic mucosa. In addition, hypoxic stress, which is frequently observed in colorectal tumours, could be responsible for the upregulation of CEACAM6 in colon cancer tissues because we observed that hypoxia induces CEACAM6 expression in a HIF-1-dependent manner 32 33. Other mechanisms involved in the regulation of CEACAM6 gene have previously been reported in IEC.…”

Section: Discussionsupporting

confidence: 60%

Diet-induced hypoxia responsive element demethylation increases CEACAM6 expression, favouring Crohn's disease-associatedEscherichia colicolonisation

Denizot

Agus

Uhrhammer

et al. 2014

Gut

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Section: Discussionsupporting

confidence: 60%

Diet-induced hypoxia responsive element demethylation increases CEACAM6 expression, favouring Crohn's disease-associatedEscherichia colicolonisation

Denizot

Agus

Uhrhammer

et al. 2014

Gut

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“…However the TAMs in colon cancer, which also presents large hypoxic areas [55], are mainly M1 type [56]. In addition, when we cultured human monocytes under hypoxic conditions in the presence of GM-CSF, no TAM re-specification was observed.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia promotes glioma-associated macrophage infiltration via periostin and subsequent M2 polarization by upregulating TGF-beta and M-CSFR

Hou

Shao³

et al. 2016

Oncotarget

147

115

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Tumor-associated macrophages (TAMs) are enriched in gliomas and help create a tumor-immunosuppressive microenvironment. A distinct M2-skewed type of macrophages makes up the majority of glioma TAMs, and these cells exhibit pro-tumor functions. Gliomas contain large hypoxic areas, and the presence of a correlation between the density of M2-polarized TAMs and hypoxic areas suggests that hypoxia plays a supportive role during TAM recruitment and induction. Here, we investigated the effects of hypoxia on human macrophage recruitment and M2 polarization. We also investigated the influence of the HIF inhibitor acriflavine (ACF) on M2 TAM infiltration and tumor progression in vivo. We found that hypoxia increased periostin (POSTN) expression in glioma cells and promoted the recruitment of macrophages. Hypoxia-inducible POSTN expression was increased by TGF-α via the RTK/PI3K pathway, and this effect was blocked by treating hypoxic cells with ACF. We also demonstrated that both a hypoxic environment and hypoxia-treated glioma cell supernatants were capable of polarizing macrophages toward a M2 phenotype. ACF partially reversed the M2 polarization of macrophages by inhibiting the upregulation of M-CSFR in macrophages and TGF-β in glioma cells under hypoxic conditions. Administering ACF also ablated tumor progression in vivo. Our findings reveal a mechanism that underlies hypoxia-induced TAM enrichment and M2 polarization and suggest that pharmacologically inhibiting HIFs may reduce M2-polarized TAM infiltration and glioma progression.

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“…Importantly, stress and hypoxia, conditions that augment the production of Mycnick, were shown to promote colon cancer invasion by inducing an EMT (Kahlert et al 2011;Hongo et al 2013). In searching for mechanisms by which Myc-nick promotes migration of colon cancer cells, we found that Myc-nick induces the expression of the actin-bundling protein fascin.…”

Section: A Potential Role For Myc-nick In Metastasismentioning

confidence: 96%

Stress-induced cleavage of Myc promotes cancer cell survival

et al. 2014

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Evasion of apoptosis is critical in Myc-induced tumor progression. Here we report that cancer cells evade death under stress by activating calpain-mediated proteolysis of Myc. This generates Myc-nick, a cytoplasmic, transcriptionally inactive cleavage product of Myc. We found conversion of Myc into Myc-nick in cell lines and tissues derived from multiple cancers. In colon cancer, the production of Myc-nick is enhanced under stress conditions such as hypoxia and nutrient deprivation. Under these conditions, ectopic expression of Myc-nick promotes anchorage-independent growth and cell survival at least in part by promoting autophagy. Myc-nick also delays colon cancer cell death after treatment with chemotherapeutic drugs such as etoposide, cisplatin, and imatinib. Furthermore, colon cancer cells expressing a cleavage-resistant form of Myc undergo extensive apoptosis but are rescued by overexpression of Myc-nick. We also found that ectopic expression of Myc-nick results in the induction of the actin-bundling protein fascin, formation of filopodia, and increased cell motility-all mediators of tumor metastasis. Myc-nick-induced survival, autophagy, and motility require Myc box II (MBII), a region of Myc-nick that recruits acetyltransferases that in turn modify cytoplasmic proteins, including a-tubulin and ATG3. Our results suggest that Myc-nick-induced survival and motility contribute to colon cancer progression and metastasis.

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Hypoxia enhances colon cancer migration and invasion through promotion of epithelial-mesenchymal transition

Cited by 47 publications

References 37 publications

Diet-induced hypoxia responsive element demethylation increases CEACAM6 expression, favouring Crohn's disease-associatedEscherichia colicolonisation

Diet-induced hypoxia responsive element demethylation increases CEACAM6 expression, favouring Crohn's disease-associatedEscherichia colicolonisation

Hypoxia promotes glioma-associated macrophage infiltration via periostin and subsequent M2 polarization by upregulating TGF-beta and M-CSFR

Stress-induced cleavage of Myc promotes cancer cell survival

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