Cancer‐associated stroma reveals prognostic biomarkers and novel insights into the tumour microenvironment of colorectal cancer and colorectal liver metastases

Brown, Kai; Xue, Aiqun; Smith, Ross C.; Samra, Jaswinder S.; Gill, Anthony J.; Hugh, Thomas J.

doi:10.1002/cam4.4452

Cited by 6 publications

(5 citation statements)

References 63 publications

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“…In particular, distant metastases and postoperative relapses within 5 years after surgery in the group with a keloid-like collagen content of more than 30% were detected in 39.5% of patients, and in the group with a keloid-like collagen content of less than 30% in 15.5% of patients. These results are consistent with scientific research [ 32 – 34 ] and suggest a close relationship between keloid-like collagen and the metastatic behavior of cancer cells.…”

Section: Discussionsupporting

confidence: 93%

Diagnostic and prognostic significance of keloid-like collagen remodeling patterns in the extracellular matrix of colorectal cancer

Imanbayev,

Iztleuov,

Kamyshanskiy

et al. 2024

Pathol. Oncol. Res.

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BackgroundThe desmoplastic reaction is considered a promising prognostic parameter for colorectal cancer. However, intermediate desmoplastic reaction is characterized by sizeable stromal heterogeneity, including both small amounts of keloid-like collagen (KC) in the fibrotic stroma and thick tufts of KC circumferentially surrounding cancer nests and occupying most of the fields of view. The present study aimed to evaluate the diagnostic and prognostic significance of KC histophenotyping with a quantitative visual assessment of its presence in the stroma of the invasive margin of TNM (The “tumor-node-metastasis” classification) stage II/III colorectal cancer (CRC).Methods and results175 resected tumors from patients with TNM stage II/III CRC were examined. Keloid-like collagen was assessed according to Ueno H. criteria. KC was assessed at the primary tumor invasive margin using Hematoxylin & Eosin and Masson’s trichrome staining. The cut-off point for KC was examined using “the best cutoff approach by log-rank test.” Using a cutoff point of 30%, we histologically divided fibrous stroma in the invasive area into two groups: “type A”—KC ≤ 0.3 and “type B”—KC>0.3. Type A stroma was observed in 48% of patients, type B—in 52%. The association between collagen amount and 5-year recurrence-free survival (5-RFS) was assessed using Cox regression analysis. Kaplan-Meier analysis and log-rank tests were used to assess the significance of survival analysis. Analysis of categorical variables showed that increased KC in CRC stroma predicted adverse outcomes for 5-RFS (hazard ratio [HR] = 3.143, 95%, confidence interval [CI] = 1.643–6.012, p = 0.001). Moreover, in Kaplan-Meier analysis, the log-rank test showed that type B exhibited worse 5-RFS than type A (p = 0.000).ConclusionKC is an independent predictor of 5-year overall and RFS in patients with TNM stage II/III CRC treated with surgery, with worse survival rates when the amount of KC increases by >30%.

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Section: Discussionsupporting

confidence: 93%

Diagnostic and prognostic significance of keloid-like collagen remodeling patterns in the extracellular matrix of colorectal cancer

Imanbayev,

Iztleuov,

Kamyshanskiy

et al. 2024

Pathol. Oncol. Res.

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“…A previous study suggested that another gene listed in our panel, NREP, was associated with poor prognosis and may be involved in the activation of cancer-associated fibroblasts and the epithelial-mesenchymal transition, with transforming growth factor β1 mediating both processes [61]. IGFBP7 was identified as a tumor stroma marker of epithelial cancers, and stromal expression of IGFBP7 was an indicator of poor survival in colorectal cancer [62,63]. When SW480 colorectal cancer cells were co-cultured with fibroblasts, IGFBP7 expression was induced in fibroblasts at both the mRNA and protein levels [64].…”

Section: Discussionmentioning

confidence: 88%

A Novel Gene List Identifies Tumors with a Stromal-Mesenchymal Phenotype and Worse Prognosis in Gastric Cancer

Canli

Uner

Kucukkaraduman

et al. 2023

Cancers

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Background: Molecular biomarkers that predict disease progression can help identify tumor subtypes and shape treatment plans. In this study, we aimed to identify robust biomarkers of prognosis in gastric cancer based on transcriptomic data obtained from primary gastric tumors. Methods: Microarray, RNA sequencing, and single-cell RNA sequencing-based gene expression data from gastric tumors were obtained from public databases. Freshly frozen gastric tumors (n = 42) and matched FFPE (formalin-fixed, paraffin-embedded) (n = 40) tissues from a Turkish gastric cancer cohort were used for quantitative real-time PCR and immunohistochemistry-based assessments of gene expression, respectively. Results: A novel list of 20 prognostic genes was identified and used for the classification of gastric tumors into two major tumor subgroups with differential stromal gene expression (“Stromal-UP” (SU) and “Stromal-DOWN” (SD)). The SU group had a more mesenchymal profile with an enrichment of extracellular matrix-related gene sets and a poor prognosis compared to the SD group. Expression of the genes within the signature correlated with the expression of mesenchymal markers ex vivo. A higher stromal content in FFPE tissues was associated with shorter overall survival. Conclusions: A stroma-rich, mesenchymal subgroup among gastric tumors identifies an unfavorable clinical outcome in all cohorts tested.

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“…Levels of TGFBI in the liver correlate with the intensity of perisinusoidal fibrosis in Stab1 KO [33]. In cancer, stromal expression of POSTN is a predictor of poorer survival in CRC [34]. In tumor bearing, Stab1 deficient mice an accumulation of POSTN was predominantly seen in the matrix of Wt31 melanoma metastases (p = 0.0159).…”

Section: Discussionmentioning

confidence: 95%

Deficiency of Stabilin-1 in the Context of Hepatic Melanoma Metastasis

Wohlfeil,

Olsavszky,

Irkens

et al. 2024

Cancers

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Background: This study analyzed the role of Stabilin-1 on hepatic melanoma metastasis in preclinical mouse models. Methods: In Stabilin-1−/− mice (Stab1 KO), liver colonization of B16F10 luc2 and Wt31 melanoma was investigated. The numbers, morphology, and vascularization of hepatic metastases and the hepatic microenvironment were analyzed by immunofluorescence. Results: While hepatic metastasis of B16F10 luc2 or Wt31 melanoma was unaltered between Stab1 KO and wildtype (Ctrl) mice, metastases of B16F10 luc2 tended to be smaller in Stab1 KO. The endothelial differentiation of both types of liver metastases was similar in Stab1 KO and Ctrl. No differences in initial tumor cell adhesion and retention to the liver vasculature were detected in the B16F10 luc2 model. Analysis of the immune microenvironment revealed a trend towards higher levels of CD45+Gr-1+ cells in Stab1 KO as compared to Ctrl in the B16F10 luc2 model. Interestingly, significantly higher levels of POSTN were found in the matrix of hepatic metastases of Wt31, while liver metastases of B16F10 luc2 showed a trend towards increased deposition of RELN. Conclusions: Hepatic melanoma metastases show resistance to Stabilin-1 targeting approaches. This suggests that anti-Stab1 therapies should be considered with respect to the tumor entity or target organs.

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Cancer‐associated stroma reveals prognostic biomarkers and novel insights into the tumour microenvironment of colorectal cancer and colorectal liver metastases

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri bution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 6 publications

References 63 publications

Diagnostic and prognostic significance of keloid-like collagen remodeling patterns in the extracellular matrix of colorectal cancer

Diagnostic and prognostic significance of keloid-like collagen remodeling patterns in the extracellular matrix of colorectal cancer

A Novel Gene List Identifies Tumors with a Stromal-Mesenchymal Phenotype and Worse Prognosis in Gastric Cancer

Deficiency of Stabilin-1 in the Context of Hepatic Melanoma Metastasis

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