Hypoxic colorectal cancer cells promote metastasis of normoxic cancer cells depending on IL-8/p65 signaling pathway

Mi, Yulong; Mu, Lei; Huang, Kaiyu; Hu, Yibing; Chang, Yan; Zhao, Hui; Ma, Chensen; Li, Xiaolan; Tao, Deding; Qin, Jianbing

doi:10.1038/s41419-020-02797-z

Cited by 23 publications

(22 citation statements)

References 45 publications

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“…MMP9 functions as an inducer of EMT through its proteolytic action on E-cadherin and concomitant loss of other epithelial markers such as vimentin and Snail. On the other hand, E-cadherin inhibition upregulates MMP2, whose expression also depends on HIF-1α, involved in the hypoxia response [25,26]. MMP2 and MMP9 mRNA, protein, and/or activity have been found increased in colorectal tumor specimens compared to normal colonic mucosa [27][28][29][30].…”

Section: Discussionmentioning

confidence: 99%

Integrated Multi-Omics Investigations of Metalloproteinases in Colon Cancer: Focus on MMP2 and MMP9

Buttacavoli

Cara

Roz

et al. 2021

IJMS

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Colorectal cancer (CRC) develops by genetic and epigenetic alterations. However, the molecular mechanisms underlying metastatic dissemination remain unclear and could benefit from multi-omics investigations of specific protein families. Matrix metalloproteinases (MMPs) are proteolytic enzymes involved in ECM remodeling and the processing of bioactive molecules. Increased MMP expression promotes the hallmarks of tumor progression, including angiogenesis, invasion, and metastasis, and is correlated with a shortened survival. Nevertheless, the collective role and the possible coordination of MMP members in CRC are poorly investigated. Here, we performed a multi-omics analysis of MMP expression in CRC using data mining and experimental investigations. Several databases were used to deeply mine different expressions between tumor and normal tissues, the genetic and epigenetic alterations, the prognostic value as well as the interrelationships with tumor immune-infiltrating cells (TIICs). A special focus was placed on to MMP2 and MMP9: their expression was correlated with immune markers and the interaction network of co-expressed genes disclosed their implication in epithelial to mesenchymal transition (EMT) and immune response. Finally, the activity levels of MMP2 and MMP9 in a cohort of colon cancer samples, including tissues and the corresponding sera, was also investigated by zymography. Our findings suggested that MMPs could have a high potency, as they are targeted in colon cancer, and might serve as novel biomarkers, especially for their involvement in the immune response. However, further studies are needed to explore the detailed biological functions and molecular mechanisms of MMPs in CRC, also in consideration of their expression and different regulation in several tissues.

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Section: Discussionmentioning

confidence: 99%

Integrated Multi-Omics Investigations of Metalloproteinases in Colon Cancer: Focus on MMP2 and MMP9

Buttacavoli

Cara

Roz

et al. 2021

IJMS

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“…CXCL8 released from pancreatic cancer induces muscle atrophy to cause involuntary body weight loss or cachexia in patients [ 156 ]. Hypoxia-treated CRC tumors show increased CXCL8 expression and promote the migration, invasion, and metastasis of normoxic CRC cells [ 157 ]. Blocking the JNK/CXCL8 pathway enhances radiation-induced necroptosis and radiotherapy efficacy in colorectal cancer [ 158 ].…”

Section: Cxcl8-cxcr1/2 Signaling Pathwaymentioning

confidence: 99%

Roles of the CXCL8-CXCR1/2 Axis in the Tumor Microenvironment and Immunotherapy

Han

Yang

et al. 2021

Molecules

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In humans, Interleukin-8 (IL-8 or CXCL8) is a granulocytic chemokine with multiple roles within the tumor microenvironment (TME), such as recruiting immunosuppressive cells to the tumor, increasing tumor angiogenesis, and promoting epithelial-to-mesenchymal transition (EMT). All of these effects of CXCL8 on individual cell types can result in cascading alterations to the TME. The changes in the TME components such as the cancer-associated fibroblasts (CAFs), the immune cells, the extracellular matrix, the blood vessels, or the lymphatic vessels further influence tumor progression and therapeutic resistance. Emerging roles of the microbiome in tumorigenesis or tumor progression revealed the intricate interactions between inflammatory response, dysbiosis, metabolites, CXCL8, immune cells, and the TME. Studies have shown that CXCL8 directly contributes to TME remodeling, cancer plasticity, and the development of resistance to both chemotherapy and immunotherapy. Further, clinical data demonstrate that CXCL8 could be an easily measurable prognostic biomarker in patients receiving immune checkpoint inhibitors. The blockade of the CXCL8-CXCR1/2 axis alone or in combination with other immunotherapy will be a promising strategy to improve antitumor efficacy. Herein, we review recent advances focusing on identifying the mechanisms between TME components and the CXCL8-CXCR1/2 axis for novel immunotherapy strategies.

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“…These two signaling cascades can activate directly and indirectly the Ser/Thr protein kinase mTOR, respectively, being the mTOR involved in the regulation of cell proliferation and survival [111]. Similarly to other solid tumors, CRC is also characterized by a hypoxic microenvironment [112]. In fact, the cancer cells have the ability of adaptation to hypoxia through the regulation of the PI3K/AKT/mTOR pathway and by the transcription factors HIF-1α and HIF-2α, whose protein expression and transcriptional activity are also regulated by mTOR [113].…”

Section: Discussionmentioning

confidence: 99%

LAT1 and ASCT2 Related microRNAs as Potential New Therapeutic Agents against Colorectal Cancer Progression

et al. 2021

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The development and progression of colorectal cancer (CRC) have been associated with genetic and epigenetic alterations and more recently with changes in cell metabolism. Amino acid transporters are key players in tumor development, and it is described that tumor cells upregulate some AA transporters in order to support the increased amino acid (AA) intake to sustain the tumor additional needs for tumor growth and proliferation through the activation of several signaling pathways. LAT1 and ASCT2 are two AA transporters involved in the regulation of the mTOR pathway that has been reported as upregulated in CRC. Some attempts have been made in order to develop therapeutic approaches to target these AA transporters, however none have reached the clinical setting so far. MiRNA-based therapies have been gaining increasing attention from pharmaceutical companies and now several miRNA-based drugs are currently in clinical trials with promising results. In this review we combine a bioinformatic approach with a literature review in order to identify a miRNA profile with the potential to target both LAT1 and ASCT2 with potential to be used as a therapeutic approach against CRC.

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Hypoxic colorectal cancer cells promote metastasis of normoxic cancer cells depending on IL-8/p65 signaling pathway

Cited by 23 publications

References 45 publications

Integrated Multi-Omics Investigations of Metalloproteinases in Colon Cancer: Focus on MMP2 and MMP9

Integrated Multi-Omics Investigations of Metalloproteinases in Colon Cancer: Focus on MMP2 and MMP9

Roles of the CXCL8-CXCR1/2 Axis in the Tumor Microenvironment and Immunotherapy

LAT1 and ASCT2 Related microRNAs as Potential New Therapeutic Agents against Colorectal Cancer Progression

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