Early heme oxygenase 1 induction delays tumour initiation and enhances DNA damage repair in liver macrophages of Mdr2−/− mice

Barikbin, R; Berkhout, L; Bolik, Julia; Schmidt-Arras, Dirk; Ernst, Thomas; Ittrich, Harald; Adam, Gerhard; Parplys, Ann Christin; Casar, Christian; Krech, Till; Karimi, Khalil; Sass, Gabriele; Tiegs, Gisa

doi:10.1038/s41598-018-33233-0

Cited by 8 publications

(8 citation statements)

References 47 publications

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“…TME macrophages in radiotherapy (9,10). Tumor-associated macrophages (TAMs) are a key component of TME and play an important role in accelerating cancer progression (11).…”

Section: M2 Macrophages Reduce the Radiosensitivity Of Head And Neck mentioning

confidence: 99%

M2 macrophages reduce the radiosensitivity of head and neck cancer by releasing HB‑EGF

Liu

et al. 2020

Oncol Rep

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The aim of the present study was to examine the potential role of human heparin-binding epidermal growth factor (HB-EGF) secreted by M2 macrophages in the development of radioresistance in head and neck squamous cell carcinoma (HNSCC). Immunohistochemistry was used to detect radiosensitivity in human papilloma virus (HPV)-positive and HPV-negative HNSCC tissues and immunohistochemical staining with specific antibodies for macrophage surface markers was used to assess the infiltration of M1 and M2 macrophages in HPV-positive and-negative HNSCC tissues. The expression of HB-EGF in HPV-positive and-negative HNSCC tissues was determined by multi-cytokine detection in order to determine the relationship between HB-EGF and radiosensitivity. M1 and M2 macrophages were co-cultured with the HNSCC cell line CAL27 and treated with HB-EGF and its neutralizing antibodies to assess radiation sensitivity. Finally, the major DNA double-strand break repair pathways required for the activation of HB-EGF and promotion of epidermal growth factor receptor (EGFR) were identified. The results revealed that radiosensitivity was higher in HPV-positive HNSCC compared with HPV-negative. There was a higher infiltration of M2 macrophages in HPV-negative HNSCC, which were revealed as the main source of HB-EGF secretion. Furthermore, it was determined that overexpression of HB-EGF induced radioresistance in HPV-negative HNSCC. HB-EGF promoted the activation of the non-homologous end-joining pathway by activating EGFR. To the best of our knowledge, this is the first study to demonstrate the association between HB-EGF and radiosensitivity in HNSCC. These results indicated that the secretion of HB-EGF by M2 macrophages could induce radioresistance of HPV-negative HNSCC.

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“…TME macrophages in radiotherapy (9,10). Tumor-associated macrophages (TAMs) are a key component of TME and play an important role in accelerating cancer progression (11).…”

Section: M2 Macrophages Reduce the Radiosensitivity Of Head And Neck mentioning

confidence: 99%

M2 macrophages reduce the radiosensitivity of head and neck cancer by releasing HB‑EGF

Liu

et al. 2020

Oncol Rep

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“…Interestingly, CoPP treatment was showed to limit cell proliferation in NG media, but not in HG media, after 5 days exposure. This was unexpected, since in the absence of any other stimulus the additions of CoPP are known not to have any effect on cell proliferation; although CoPP had recently been demonstrated to delay tumor growth (Barikbin et al 2018 ). CoPP treatment also significantly decreased the migration rate of HaCaT cultured in NG media, as opposed to when the cells were cultured in HG media, in which the CoPP had significantly enhanced migratory capacity.…”

Section: Discussionmentioning

confidence: 99%

Cobalt protoporphyrin promotes human keratinocyte migration under hyperglycemic conditions

Fang

Lai²,

Chen³

et al. 2022

Mol Med

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Background Complete healing of diabetic wounds continues to be a clinically unmet need. Although robust therapies such as stem cell therapy and growth factor treatment are clinically applied, these treatments are costly for most diabetic wound patients. Therefore, a cheaper alternative is needed. Cobalt protoporphyrin (CoPP) has recently been demonstrated to promote tissue regeneration. In this study, the therapeutic benefits of CoPP in diabetic wound healing were examined. Methods An in vitro wound healing model that mimics re-epithelialization was established to examine the effect of CoPP on the migratory capability of human keratinocytes (HaCaT) in either normal glucose (NG) or high glucose (HG) media, as well as in the presence of either H2O2 or lipopolysaccharide (LPS). At the end of the migration assays, cells were collected and subjected to Western blotting analysis and immunostaining. Results HaCaT were found to migrate significantly more slowly in the HG media compared to the NG media. CoPP treatment was found to enhance cell migration in HG media, but was found to decrease cell migration and proliferation when HaCaT were cultured in NG media. CoPP treatment induced high levels of expression of Nrf-2/HO-1 and FoxO1 in HaCaT cultured in either glucose concentration, although the FoxO1 expression was found to be significantly higher in HaCaT that underwent the migration assay in NG media compared to those in HG media. The higher level of FoxO1 expression seen in CoPP-treated HaCaT cultured in NG media resulted in upregulation of CCL20 and downregulation of TGFβ1. In contrast, HaCaT migrated in HG media were found to have high levels of expression of TGFβ1, and low levels of expression of CCL20. Interestingly, in the presence of H2O2, CoPP-pretreated HaCaT cultured in either NG or HG media had similar expression level of Nrf-2/HO-1 and FoxO1 to each other. Moreover, the anti-apoptotic effect of CoPP pretreatment was noticed in HaCaT cultured in either glucose concentration. Additionally, CoPP pretreatment was shown to promote tight junction formation in HaCaT suffering from LPS-induced damage. Conclusions CoPP enhances cell migratory capacity under hyperglycemic conditions, and protects cells from oxidative and LPS-induced cellular damage in HG media containing either H2O2 or LPS.

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“…Second, we showed that overexpression of HO-1 decreases tumorigenicity in secondary and tertiary recipients, probably due to reduced self-renewal of melanoma cells. Early induction of HO-1 in Mdr2 −/− mice (the model of chronic liver inflammation and inflammation-induced tumor development) delayed the initiation of liver tumors through amelioration of chronic inflammation [ 86 ]. Moreover, in chemically induced squamous cell carcinoma, HO-1 KO mice developed lesions earlier than WT animals [ 87 ], suggesting that HO-1 can delay the initiation of tumor formation.…”

Section: Discussionmentioning

confidence: 99%

Heme Oxygenase-1 Has a Greater Effect on Melanoma Stem Cell Properties Than the Expression of Melanoma-Initiating Cell Markers

Kusienicka

Bukowska-Straková

Cieśla

et al. 2022

IJMS

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Melanoma-initiating cells (MICs) contribute to the tumorigenicity and heterogeneity of melanoma. MICs are identified by surface and functional markers and have been shown to display cancer stem cell (CSC) properties. However, the existence of MICs that follow the hierarchical CSC model has been questioned by studies showing that single unselected melanoma cells are highly tumorigenic in xenotransplantation assays. Herein, we characterize cells expressing MIC markers (CD20, CD24, CD133, Sca-1, ABCB1, ABCB5, ALDHhigh) in the B16-F10 murine melanoma cell line. We use flow cytometric phenotyping, single-cell sorting followed by in vitro clonogenic assays, and syngeneic in vivo serial transplantation assays to demonstrate that the expression of MIC markers does not select CSC-like cells in this cell line. Previously, our group showed that heme-degrading enzyme heme oxygenase-1 (HO-1) can be upregulated in melanoma and increase its aggressiveness. Here, we show that HO-1 activity is important for non-adherent growth of melanoma and HO-1 overexpression enhances the vasculogenic mimicry potential, which can be considered protumorigenic activity. However, HO-1 overexpression decreases clone formation in vitro and serial tumor initiation in vivo. Thus, HO-1 plays a dual role in melanoma, improving the progression of growing tumors but reducing the risk of melanoma initiation.

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Early heme oxygenase 1 induction delays tumour initiation and enhances DNA damage repair in liver macrophages of Mdr2−/− mice

Cited by 8 publications

References 47 publications

M2 macrophages reduce the radiosensitivity of head and neck cancer by releasing HB‑EGF

M2 macrophages reduce the radiosensitivity of head and neck cancer by releasing HB‑EGF

Cobalt protoporphyrin promotes human keratinocyte migration under hyperglycemic conditions

Heme Oxygenase-1 Has a Greater Effect on Melanoma Stem Cell Properties Than the Expression of Melanoma-Initiating Cell Markers

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