Vascular Invasion and Stromal S100A4 Expression at the Invasive Front of Colorectal Cancer are Novel Determinants and Tumor Prognostic Markers

Sugai, Tamotsu; Yamada, Noriyuki; Eizuka, Makoto; Sugimoto, Ryo; Uesugi, Noriyuki; Osakabe, Mitsumasa; Ishida, Kazuyuki; Otsuka, Kuniko; Sasaki, Akira; Matsumoto, Takayuki

doi:10.7150/jca.18685

Cited by 21 publications

(39 citation statements)

References 31 publications

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“…Thus, we took RAS and BRAF mutations together to assess its predictive value. It showed no statistically significant relationship between the RAS/BRAF mutations and recurrence from surgical resection, but we observed that patients with vascular tumor thrombus had worse DFS than patients without vascular tumor thrombus which was consistent with previous findings [ 19 – 21 ]. Since ctDNA KRAS had a concordance of 81.25% compared with tumor tissue in our study, we further aimed to analyze the prognostic role of ctDNA gene mutation status in subsequent first-line palliative chemotherapy.…”

Section: Discussionsupporting

confidence: 92%

RAS/BRAF Circulating Tumor DNA Mutations as a Predictor of Response to First-Line Chemotherapy in Metastatic Colorectal Cancer Patients

Yao

Zang

et al. 2018

Canadian Journal of Gastroenterology and Hepatology

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Background Since circulating tumor DNA (ctDNA) offers clear advantages as a minimally invasive method for tumor monitoring compared with tumor tissue, we aimed to evaluate genotyping ctDNA using a next-generation sequencing- (NGS-) based panel to identify the prognostic value of mutation status in metastatic colorectal cancer (mCRC) patients with primary tumor resected and with subsequent lines of treatment in this study. Methods 76 mCRC patients treated in Beijing Chao-Yang Hospital from 2011 to 2017 were enrolled. Genotyping of RAS/BRAF in tumor tissue and ctDNA was determined by ARMS PCR and with a 40-gene panel using NGS, respectively. Patient clinicopathologic features and RAS/BRAF gene mutation status were evaluated by survival analysis for disease-free survival (DFS) and progression-free survival (PFS). Results Among 76 patients, KRAS distributions were not significantly correlated with any clinicopathologic features. The concordance between tumor tissue and ctDNA KRAS mutation was 81.25%. Mutations of RAS/BRAF had no significant impact on DFS after surgery (hazard ratio (HR), 1.205; 95% CI, 0.618 to 2.349; P = 0.5837) but prognosticated poorer PFS in subsequent first-line therapy (HR, 3.351; 95% CI, 1.172 to 9.576; P = 0.024). Conclusion ctDNA was comparable with tumor tissue for mutation detection. RAS/BRAF mutations detected in ctDNA predict a worse PFS in mCRC patients with first-line chemotherapy. Our results provide support for the prognostic value of RAS/BRAF ctDNA mutation detection in mCRC patients.

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Section: Discussionsupporting

confidence: 92%

RAS/BRAF Circulating Tumor DNA Mutations as a Predictor of Response to First-Line Chemotherapy in Metastatic Colorectal Cancer Patients

Yao

Zang

et al. 2018

Canadian Journal of Gastroenterology and Hepatology

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“…The most widely used marker for CAFs is α-SMA, a specific marker of myofibroblasts 11 - 13 . Additional markers for CAFs include CD10 28 , 29 , podoplanin 30 , FSP1 24 , 31 , and AEBP1; these markers are also thought to be associated with tumor invasion and metastasis 32 , 33 . In addition, EMT-related markers, including TWIST1 34 and ZEB1 35 , were also used in the present study because EMT-related proteins may also be markers of CAFs (e.g., co-expression of CAF- and EMT-related proteins is observed in the same fibroblasts).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, EMT-related markers, including TWIST1 34 and ZEB1 35 , were also used in the present study because EMT-related proteins may also be markers of CAFs (e.g., co-expression of CAF- and EMT-related proteins is observed in the same fibroblasts). The antibodies we used in this study are widely available and are reliably and reproducibly used in studies of CRC 24 , 28 , 31 , 32 . Thus, these markers, i.e., α-SMA, CD10, podoplanin, FSP1, AEBP1, TWIST1, and ZEB1, are thought to be suitable for identifying the roles of CAFs and the EMT in SiCRC.…”

Section: Discussionmentioning

confidence: 99%

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Analysis of the expression of cancer-associated fibroblast- and EMT-related proteins in submucosal invasive colorectal cancer

Sugai¹,

Uesugi²,

Kitada³

et al. 2018

J. Cancer

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Objective: Recent studies have shown that cancer-associated fibroblasts (CAFs) and the epithelial-mesenchymal transition (EMT) play important roles in the progression and metastasis of CRC. Although prediction of lymph node metastasis in submucosal invasive colorectal cancer (SiCRC) is important, the relationships of CAF and EMT with lymph node metastasis of SiCRC have not yet been examined. Here, we aimed to analyze the expression patterns of CAF- and EMT-related proteins in SiCRC.Materials and Methods: The expression of CAF-related markers, including α-smooth muscle actin, CD10, podoplanin, fibroblast specific protein 1, and adipocyte enhancer-binding protein 1, and EMT-related proteins [zinc finger protein SNAI2 (ZEB1) and twist-related protein 1 (TWIST1) in SiCRC with (n = 29) or without (n = 80) lymph node metastasis was examined by immunohistochemistry. We examined the expression patterns of biomarkers using hierarchical cluster analysis. Consequently, four subgroups were established based on the expression patterns of CAF- and EMT-related markers, and the associations of these subgroups with clinicopathological variables.Results: In multivariate analysis, subgroup 2, which was characterized by high expression of all markers, was correlated with lymph node metastasis (p < 0.01). Next, we examined the associations of individual biomarkers with lymph node metastasis. Multivariate analysis showed that moderately differentiated adenocarcinoma was significantly associated with lymph node metastasis (p < 0.05).Conclusions: Our findings showed that expression patterns of CAF markers and EMT-related proteins may allow for stratification of patients into risk categories for lymph node metastasis in SiCRC.

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“…The tumor invasion front is the area at the edge of the tumor which represents a critical interface at tumor progression and tumor cell dissemination (22). Changes in the environment of the tumor invasion front also affect the behavior of tumor cells and patient prognosis (23).…”

Section: Introductionmentioning

confidence: 99%

Prognostic significance of abnormal matrix collagen remodeling in colorectal cancer based on histologic and bioinformatics analysis

Liang

Huang

et al. 2020

Oncol Rep

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As the major component of the tumor matrix, collagen greatly influences tumor invasion and prognosis. The present study compared the remodeling of collagen and collagenase in 56 patients with colorectal cancer (CRC) using Sirius red stain and immunohistochemistry, exploring the relationship between collagen remodeling and the prognosis of CRC. Weak or strong changes in collagen fiber arrangement in birefringence were observed. With the exception of a higher density, weak changes equated to a similar arrangement in normal collagen, while strong changes facilitated cross-linking into bundles. Compared with normal tissues, collagen I (COL I) and III (COL III) deposition was significantly increased in CRC tissues, and was positively correlated with the metastasis status. In tissues without distant metastasis, collagen IV (COL IV) levels were higher than that in normal tissues, while in tissues with distant metastasis, collagen IV expression was significantly lower. Furthermore, the expression of matrix metalloproteinase (MMP)-1, MMP-2, MMP-7, MMP-9 and lysyl oxidase-like 2 (LOXL2) was found to be elevated in the cancer stroma, which contributed to the hyperactive remodeling of collagen. The association between collagen-related genes and the occurrence and prognosis of CRC were analyzed using biometric databases. The results indicated that patients with upregulated expression of a combination of coding genes for collagen and collagenase exhibited poorer overall survival times. The coding genes COL1A1-2, COL3A1, COL4A3, COL4A6 and MMP2 may therefore be used as biomarkers to predict the prognosis of patients with CRC. Furthermore, the results of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis suggest that collagen may promote tumor development by activating platelets. Collectively, the abnormal collagen remodeling, including associated protein and coding genes is associated with the tumorigenesis and metastasis, affecting the prognosis of patients with CRC.

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Vascular Invasion and Stromal S100A4 Expression at the Invasive Front of Colorectal Cancer are Novel Determinants and Tumor Prognostic Markers

Cited by 21 publications

References 31 publications

RAS/BRAF Circulating Tumor DNA Mutations as a Predictor of Response to First-Line Chemotherapy in Metastatic Colorectal Cancer Patients

RAS/BRAF Circulating Tumor DNA Mutations as a Predictor of Response to First-Line Chemotherapy in Metastatic Colorectal Cancer Patients

Analysis of the expression of cancer-associated fibroblast- and EMT-related proteins in submucosal invasive colorectal cancer

Prognostic significance of abnormal matrix collagen remodeling in colorectal cancer based on histologic and bioinformatics analysis

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