Cancer-Associated Stromal Fibroblast-Derived Transcriptomes Predict Poor Clinical Outcomes and Immunosuppression in Colon Cancer

Wang, Jie; Akter, Rehana; Shahriar, Md. Fahim; Uddin, Nazim

doi:10.3389/pore.2022.1610350

Cited by 15 publications

(6 citation statements)

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“…Further analyses allowed to determine that CTHRC1 is highly expressed by cancer-associated fibroblasts (CAFs) and it is present in the vascular tissue surrounding the gastric lesions, where it may favor macrophage infiltration though the interaction with CAFs via the GRN/TNFRSF1A and AnxA1/FPR1 pathways ( 42 ). CAFs are likely the major source of CTHRC1 also in CRC, in which CTHRC1 expression is upregulated and it takes part in a gene-based signature with prognostic value ( 41 ). Indeed, the upregulation of CTHRC1, together with that of the Placental Derived Growth Factor C (PDGFC), PDZ and LIM Domain 3 (PDLIM3), Neurotrimin (NTM), and Solute Carrier Family 16 Member 3 (SLC16A3) genes, positively correlates with M2 macrophages, regulatory T cells (Tregs), and myeloid-derived suppressor cells (MDSCs) infiltration, as well as T cell exhaustion and associates with poor CRC patient survival ( 41 ).…”

Section: Resultsmentioning

confidence: 99%

“…CAFs are likely the major source of CTHRC1 also in CRC, in which CTHRC1 expression is upregulated and it takes part in a gene-based signature with prognostic value ( 41 ). Indeed, the upregulation of CTHRC1, together with that of the Placental Derived Growth Factor C (PDGFC), PDZ and LIM Domain 3 (PDLIM3), Neurotrimin (NTM), and Solute Carrier Family 16 Member 3 (SLC16A3) genes, positively correlates with M2 macrophages, regulatory T cells (Tregs), and myeloid-derived suppressor cells (MDSCs) infiltration, as well as T cell exhaustion and associates with poor CRC patient survival ( 41 ). Taken together, these two papers confirm the immunosuppressive role of CTHRC1 in gastrointestinal cancers.…”

Section: Resultsmentioning

confidence: 99%

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The entanglement of extracellular matrix molecules and immune checkpoint inhibitors in cancer: a systematic review of the literature

Fejza,

Carobolante,

Poletto

et al. 2023

Front. Immunol.

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IntroductionImmune-checkpoint inhibitors (ICIs) have emerged as a core pillar of cancer therapy as single agents or in combination regimens both in adults and children. Unfortunately, ICIs provide a long-lasting therapeutic effect in only one third of the patients. Thus, the search for predictive biomarkers of responsiveness to ICIs remains an urgent clinical need. The efficacy of ICIs treatments is strongly affected not only by the specific characteristics of cancer cells and the levels of immune checkpoint ligands, but also by other components of the tumor microenvironment, among which the extracellular matrix (ECM) is emerging as key player. With the aim to comprehensively describe the relation between ECM and ICIs’ efficacy in cancer patients, the present review systematically evaluated the current literature regarding ECM remodeling in association with immunotherapeutic approaches.MethodsThis review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines and was registered at the International Prospective Register of Systematic Reviews (PROSPERO, CRD42022351180). PubMed, Web of Science, and Scopus databases were comprehensively searched from inception to January 2023. Titles, abstracts and full text screening was performed to exclude non eligible articles. The risk of bias was assessed using the QUADAS-2 tool.ResultsAfter employing relevant MeSH and key terms, we identified a total of 5070 studies. Among them, 2540 duplicates, 1521 reviews or commentaries were found and excluded. Following title and abstract screening, the full text was analyzed, and 47 studies meeting the eligibility criteria were retained. The studies included in this systematic review comprehensively recapitulate the latest observations associating changes of the ECM composition following remodeling with the traits of the tumor immune cell infiltration. The present study provides for the first time a broad view of the tight association between ECM molecules and ICIs efficacy in different tumor types, highlighting the importance of ECM-derived proteolytic products as promising liquid biopsy-based biomarkers to predict the efficacy of ICIs.ConclusionECM remodeling has an important impact on the immune traits of different tumor types. Increasing evidence pinpoint at ECM-derived molecules as putative biomarkers to identify the patients that would most likely benefit from ICIs treatments.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022351180, identifier CRD42022351180.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

The entanglement of extracellular matrix molecules and immune checkpoint inhibitors in cancer: a systematic review of the literature

Fejza,

Carobolante,

Poletto

et al. 2023

Front. Immunol.

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“…In this study, we identified a novel gene signature associated with CAF infiltration that may serve as a potential prognostic marker and predictor of therapeutic response. Unlike the conventional differential gene expression (DEG) strategy for screening hub CAF markers ( 60 ), WGCNA assesses the connection between co-expressed genes and sample phenotypes. We utilized numerous deconvolution algorithms to assess the CAF abundance of each sample as its characteristic.…”

Section: Discussionmentioning

confidence: 99%

A WGCNA-based cancer-associated fibroblast risk signature in colorectal cancer for prognosis and immunotherapy response

Lv,

Hu,

Zheng

et al. 2023

Transl Cancer Res

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Background Cancer-associated fibroblasts (CAFs) are notably involved in colorectal cancer (CRC) tumorigenesis, progression, and treatment failure. In this article, we report the in silico development of a CAF-related prognostic signature for CRC. Methods We separately downloaded CRC transcription data from The Cancer Genome Atlas and the Gene Expression Omnibus database. Deconvolution algorithms, including Estimating the Proportions of Immune and Cancer Cells and the Microenvironment Cell Population-counter, were used to calculate CAF abundance, while the Estimation of Stromal and Immune cells in Malignant Tumor tissues using Expression algorithm was used to calculate the stromal score. Weighted gene co-expression network analysis (WGCNA) and the least absolute shrinkage and selection operator algorithm were used to identify CAF-related genes and prognostic signatures. Results We identified a three-gene, prognostic, CAF-related signature and defined risk groups based on the Riskscores. Multidimensional validations were applied to evaluate the robustness of the signature and its correlation with clinical parameters. We utilized Tumor Immune Dysfunction and Exclusion (TIDE) and oncoPredict algorithms to predict therapy responses and found that patients in low-risk groups are more sensitive to immunotherapy and chemotherapy drugs such as 5-fluorouracil and oxaliplatin. Finally, we used the Cancer Cell Line Encyclopedia and Human Protein Atlas databases to evaluate the mRNA and protein levels encoded by the signature genes. Conclusions This novel CAF-related three-gene signature is expected to become a potential prognostic biomarker in CRC and predict chemotherapy and immunotherapy responses. It may be of considerable value for studying the tumor microenvironment in CRC.

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“…Similar to this, elevated FBN2 expression was discovered to be a risk factor for stomach and lung cancer [ 44 , 45 ]. Additionally, it also has been demonstrated that FBN2 might serve as tumour‐suppressive effects and is a characteristic basement membrane marker in several types of cancer [ 46 , 47 ]. Additionally, it has been suggested that FBN2 may be a highly effective diagnostic tool for rhabdomyosarcoma and smooth muscle sarcoma [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

A comprehensive analysis of FBN2 in bladder cancer: A risk factor and the tumour microenvironment influencer

Lai

et al. 2023

IET Systems Biology

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Bladder cancer (BLCA) is a common and difficult‐to‐manage disease worldwide. Most common type of BLCA is urothelial carcinoma (UC). Fibrillin 2 (FBN2) was first discovered while studying Marfan syndrome, and its encoded products are associated with elastin fibres. To date, the role of FBN2 in BLCA remains unclear. The authors first downloaded data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). The patients were divided into high FBN2 expression and low FBN2 expression groups, and the survival curve, clinical characteristics, tumour microenvironment (TME), and immune cell differences were analysed between the two groups. Then, the differentially expressed genes (DEGs) were filtered, and functional enrichment for DEGs was performed. Finally, chemotherapy drug susceptibility analysis based on the high and low FBN2 groups was conducted. The authors found upregulated expression of FBN2 in BLCA and proved that FBN2 could be an independent prognostic factor for BLCA. TME analysis showed that the expression of FBN2 affects several aspects of the TME. The upregulated expression of FBN2 was associated with a high stromal score, which may lead to immunosuppression and be detrimental to immunotherapy. In addition, the authors found that NK cells resting, macrophage M0 infiltration, and other phenomena of immune cell infiltration appeared in the high expression group of FBN2. The high expression of FBN2 was related to the high sensitivity of some chemotherapy drugs. The authors systematically investigated the effects and mechanisms of FBN2 on BLCA and provided a new understanding of the role of FBN2 as a risk factor and TME influencer in BLCA.

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Cancer-Associated Stromal Fibroblast-Derived Transcriptomes Predict Poor Clinical Outcomes and Immunosuppression in Colon Cancer

Cited by 15 publications

References 77 publications

The entanglement of extracellular matrix molecules and immune checkpoint inhibitors in cancer: a systematic review of the literature

The entanglement of extracellular matrix molecules and immune checkpoint inhibitors in cancer: a systematic review of the literature

A WGCNA-based cancer-associated fibroblast risk signature in colorectal cancer for prognosis and immunotherapy response

A comprehensive analysis of FBN2 in bladder cancer: A risk factor and the tumour microenvironment influencer

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