Microenvironmental Reactive Oxygen Species in Colorectal Cancer: Involved Processes and Therapeutic Opportunities

Sorolla, Maria Alba; Hidalgo, Iván Astola; Sorolla, Anabel; Montal, Robert; Pallisé, Ona; Salud, Antonieta; Parisi, Eva

doi:10.3390/cancers13205037

Cited by 29 publications

(27 citation statements)

References 158 publications

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“…Neutrophil oxidative burst has been reported to promote tumor progression [ 17 ]. As shown in Figure 3 a, an increase in intracellular ROS levels was detected in dHL60 cells treated with A375 CSC–CM.…”

Section: Resultsmentioning

confidence: 99%

Melanoma Stem Cells Educate Neutrophils to Support Cancer Progression

Anselmi

Fontana

Marzagalli

et al. 2022

Cancers

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Background: It is now well-established that cancer stem cells (CSCs) can support melanoma progression by reshaping the tumor immune microenvironment. However, the molecular mechanisms underlying the crosstalk between melanoma SCs and cancer-associated neutrophils have not been elucidated yet. Methods: The aim of the present study was to unravel the role of melanoma SCs in neutrophil polarization. HL60 neutrophil-like (dHL60) cells were treated with conditioned medium from A375 melanoma SCs (CSC-CM), and their phenotype was investigated. Results: We demonstrated that CSC-CM could specifically activate immune cells by increasing CD66b and CD11b expression. In particular, we revealed that A375 CSCs could release various soluble factors, namely TGF-β, IL-6, and IL-8, able to promote the recruitment of neutrophils and their switch toward an N2 phenotype characterized by the activation of ERK, STAT3, and P38 pathways and the overexpression of CXCR2 and NF-kB. Moreover, after exposure to CSC-CM, dHL60 cells exhibited enhanced ROS production and NET release, without undergoing cell death; increased secretion of MMP-9 and pro-inflammatory cytokines was also observed. Finally, CSC-CM-activated neutrophils endowed A375 cells with stemness traits, stimulating both sphere formation and ABCG2 expression. Conclusion: Collectively, our results suggest that melanoma SCs can prime neutrophils to support cancer progression.

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Section: Resultsmentioning

confidence: 99%

Melanoma Stem Cells Educate Neutrophils to Support Cancer Progression

Anselmi

Fontana

Marzagalli

et al. 2022

Cancers

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“…Many chemotherapeutic agents act as DNA damage inducers, leading to cancer cell death. Inactivation of GSTs often induces ROS production that causes DNA damage ( 29 ). However, chemotherapeutic agents may also modulate GST expression and ROS production ( 5 , 30 ).…”

Section: Resultsmentioning

confidence: 99%

“…The tumor microenvironment is enriched with ROS that have multifaceted roles in cancer cell proliferation, apoptosis, angiogenesis, and metastasis ( 29 ). GSTs, as anti-oxidant enzymes, can eliminate ROS and protect cells against ROS-induced apoptosis ( 5 , 8 ).…”

Section: Discussionmentioning

confidence: 99%

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Glutathione S-Transferase Alpha 4 Promotes Proliferation and Chemoresistance in Colorectal Cancer Cells

Zhang

Hua

et al. 2022

Front. Oncol.

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Glutathione S-transferase alpha 4 (GSTA4) is a phase II detoxifying enzyme that is overexpressed in colorectal cancer (CRC) and regulated by the oncogenic transcription factor AP-1. However, the role of GSTA4 in these CRC cells remains unclear. In this study, we investigated the roles of GSTA4 in the CRC cells by inactivating GSTA4 in HCT116 human CRC cells (Defined as HCT116ΔGSTA4) using the CRISPR/Cas9 gene editing. Cell proliferation, clonogenicity, and susceptibility to chemotherapeutic drugs were analyzed in vitro and in a xenograft model. The results showed that loss of GSTA4 significantly decreased cell proliferation and clonogenicity, whereas it increased intracellular reactive oxygen species and cell susceptibility to 5-fluorouracil (5-FU) and oxaliplatin. Additionally, exposure of HCT116ΔGSTA4 cells to 5-FU increased the expression of γH2AX, a hallmark of double-stranded DNA breaks. In contrast, no remarkably increased γH2AX was noted in oxaliplatin-treated HCT116ΔGSTA4 cells compared with HCT116 cells. Moreover, loss of GSTA4 blocked the AKT and p38 MAPK pathways, leading to proliferative suppression. Finally, the xenograft model showed decreased tumor size for HCT116ΔGSTA4 cells compared with HCT116 cells, confirming in vitro findings. These findings suggest that GSTA4 is capable of promoting proliferation, tumorigenesis, and chemoresistance and is a potential target for CRC therapy.

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“…Recent studies on basic tumor biology have shown that the tumor microenvironment (TME) plays a vital role in remodeling metastatic capacity and determining tumor prognosis (10)(11)(12). Cancer-associated fibroblasts (CAFs) are the major cellular components of the TME and have recently been regarded as critical factors to modulate the TME (13,14).…”

Section: Introductionmentioning

confidence: 99%

Development and Validation of a Novel Prognostic Nomogram Combined With Desmoplastic Reaction for Synchronous Colorectal Peritoneal Metastasis

et al. 2022

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PurposeThe prognostic value of desmoplastic reaction (DR) has not been investigated in colorectal cancer (CRC) patients with synchronous peritoneal metastasis (SPM). The present study aimed to identify whether DR can predict overall survival (OS) and develop a novel prognostic nomogram.MethodsCRC patients with SPM were enrolled from a single center between July 2007 and July 2019. DR patterns in primary tumors were classified as mature, intermediate, or immature according to the existence and absence of keloid-like collagen or myxoid stroma. Cox regression analysis was used to identify independent factors associated with OS and a nomogram was developed subsequently.ResultsOne hundred ninety-eight and 99 patients were randomly allocated into the training and validation groups. The median OS in the training group was 36, 25, and 12 months in mature, intermediate, and immature DR categories, respectively. Age, T stage, extraperitoneal metastasis, differentiation, cytoreductive surgery (CRS), hyperthermic intraperitoneal chemotherapy (HIPEC), and DR categorization were independent variables for OS, based on which the nomogram was developed. The C-index of the nomogram in the training and validation groups was 0.773 (95% CI 0.734–0.812) and 0.767 (95% CI 0.708–0.826). The calibration plots showed satisfactory agreement between the actual outcome and nomogram-predicted OS probabilities in the training and validation cohorts.ConclusionsDR classification in the primary tumor is a potential prognostic index for CRC patients with SPM. The novel prognostic nomogram combined with DR classification has good discrimination and accuracy in predicting the OS for CRC patients with SPM.

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Microenvironmental Reactive Oxygen Species in Colorectal Cancer: Involved Processes and Therapeutic Opportunities

Cited by 29 publications

References 158 publications

Melanoma Stem Cells Educate Neutrophils to Support Cancer Progression

Melanoma Stem Cells Educate Neutrophils to Support Cancer Progression

Glutathione S-Transferase Alpha 4 Promotes Proliferation and Chemoresistance in Colorectal Cancer Cells

Development and Validation of a Novel Prognostic Nomogram Combined With Desmoplastic Reaction for Synchronous Colorectal Peritoneal Metastasis

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