The prognostic value of the stem-like group in colorectal cancer using a panel of immunohistochemistry markers

Ong, Chee Wee; Chong, Pek Yoon; McArt, Darragh G.; Chan, Jason Yongsheng; Tan, Hwee Hoon; Kumar, Alan Prem; Chung, Maxey C. M.; Clément, Marie‐Véronique; Soong, Richie; Schaeybroeck, Sandra Van; Waugh, David J.; Johnston, Patrick G.; Dunne, Philip D.; Salto-Tellez, Manuel

doi:10.18632/oncotarget.3497

Cited by 15 publications

(8 citation statements)

References 30 publications

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“…2). The majority support a positive impact on prognosis associated with extensive memory T-cell infiltration in the same cancers we discussed earlier, eg, CRC (Anitei et al, 2014;Boissi ere-Michot et al, 2014;Correale et al, 2012;Kim, Bae, et al, 2015;Ling et al, 2014;Ong et al, 2015;Shinto et al, 2014), bladder (Ingels et al, 2014), breast de Kruijf et al, 2013;García-Martínez et al, 2014;Kim et al, 2013;Mohammed et al, 2013;Park et al, 2012;Rathore et al, 2014;Seo et al, 2013;West et al, 2013), Merkel cell carcinoma (Paulson et al, 2014), glioma (Han et al, 2014), pancreatic (Ino et al, 2013;Tang et al, 2014), head and neck (Balermpas et al, 2014;Czystowska et al, 2013;Millrud et al, 2012;Wallis et al, 2015), cervical (Origoni et al, 2013), NSCLC Hald et al, 2013), gastric Feichtenbeiner et al, 2014;Kim et al, 2014), ovarian (Bachmayr-Heyda et al, 2013;Nielsen et al, 2012;Preston et al, 2013), and HCC (Cariani et al, 2012;Chen et al, 2012;Guo et al, 2007;Huang et al, 2012) (Table 1 and Fig. 2).…”

Section: Role Of T Cellssupporting

confidence: 65%

Immune Contexture, Immunoscore, and Malignant Cell Molecular Subgroups for Prognostic and Theranostic Classifications of Cancers

Becht¹,

Giraldo²,

Germain³

et al. 2016

Advances in Immunology

172

136

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Section: Role Of T Cellssupporting

confidence: 65%

Immune Contexture, Immunoscore, and Malignant Cell Molecular Subgroups for Prognostic and Theranostic Classifications of Cancers

Becht¹,

Giraldo²,

Germain³

et al. 2016

Advances in Immunology

172

136

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“…These data collectively challenge the general assumption that tumors classified as mesenchymal, or in the CMS4 subgroup, have undergone widespread EMT, resulting in lower levels of epithelial-associated traits in the tumor cell compartment, when actually these tumors have a higher component of stromal (particularly fibroblast) infiltration. Although IHC-based analysis of colorectal cancer tumors has shown that neoplastic epithelial cells expressing stem-like properties have a poor prognosis (15)(16)(17), our findings emphasize that the CMS4 subgroup represents tumors with higher transcription levels of mesenchymal-associated genes, which can be attributed to their overall stromal-rich, and in particular fibroblast, architecture.…”

Section: Discussionmentioning

confidence: 55%

Challenging the Cancer Molecular Stratification Dogma: Intratumoral Heterogeneity Undermines Consensus Molecular Subtypes and Potential Diagnostic Value in Colorectal Cancer

Dunne

McArt

Bradley

et al. 2016

Clinical Cancer Research

Self Cite

141

143

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Purpose: A number of independent gene expression profiling studies have identified transcriptional subtypes in colorectal cancer with potential diagnostic utility, culminating in publication of a colorectal cancer Consensus Molecular Subtype classification. The worst prognostic subtype has been defined by genes associated with stem-like biology. Recently, it has been shown that the majority of genes associated with this poor prognostic group are stromal derived. We investigated the potential for tumor misclassification into multiple diagnostic subgroups based on tumoral region sampled.Experimental Design: We performed multiregion tissue RNA extraction/transcriptomic analysis using colorectal-specific arrays on invasive front, central tumor, and lymph node regions selected from tissue samples from 25 colorectal cancer patients.Results: We identified a consensus 30-gene list, which represents the intratumoral heterogeneity within a cohort of primary colorectal cancer tumors. Using a series of online datasets, we showed that this gene list displays prognostic potential HR ¼ 2.914 (confidence interval 0.9286-9.162) in stage II/III colorectal cancer patients, but in addition, we demonstrated that these genes are stromal derived, challenging the assumption that poor prognosis tumors with stemlike biology have undergone a widespread epithelial-mesenchymal transition. Most importantly, we showed that patients can be simultaneously classified into multiple diagnostically relevant subgroups based purely on the tumoral region analyzed.Conclusions: Gene expression profiles derived from the nonmalignant stromal region can influence assignment of colorectal cancer transcriptional subtypes, questioning the current molecular classification dogma and highlighting the need to consider pathology sampling region and degree of stromal infiltration when employing transcription-based classifiers to underpin clinical decision making in colorectal cancer.

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“…CD44 is also the main receptor of the ECM component hyaluronan [ 44 ], and it has been shown that expression of CD44 on tumor cells correlate with cancer cell adhesion to endothelial cells and also with metastasis [ 45 ]. In a previous study, a cluster of stem-like factors, including SOX2 and CD44, identified patients with a worse prognosis [ 46 ]. We plan to further investigate the role of SOX2 in cancer stem cell differentiation and tumor progression.…”

Section: Discussionmentioning

confidence: 99%

SOX2 expression is associated with a cancer stem cell state and down-regulation of CDX2 in colorectal cancer

et al. 2016

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BackgroundTo improve current treatment strategies for patients with aggressive colorectal cancer (CRC), the molecular understanding of subgroups of CRC with poor prognosis is of vast importance. SOX2 positive tumors have been associated with a poor patient outcome, but the functional role of SOX2 in CRC patient prognosis is still unclear.MethodsAn in vitro cell culture model expressing SOX2 was used to investigate the functional role of SOX2 in CRC. In vitro findings were verified using RNA from fresh frozen tumor tissue or immunohistochemistry on formalin fixed paraffin embedded (FFPE) tumor tissue from a cohort of 445 CRC patients.ResultsUsing our in vitro model, we found that SOX2 expressing cells displayed several characteristics of cancer stem cells; such as a decreased proliferative rate, a spheroid growth pattern, and increased expression of stem cell markers CD24 and CD44. Cells expressing SOX2 also showed down-regulated expression of the intestinal epithelial marker CDX2. We next evaluated CDX2 expression in our patient cohort. CDX2 down-regulation was more often found in right sided tumors of high grade and high stage. Furthermore, a decreased expression of CDX2 was closely linked to MSI, CIMP-high as well as BRAF mutated tumors. A decreased expression of CDX2 was also, in a stepwise manner, strongly correlated to a poor patient prognosis. When looking at SOX2 expression in relation to CDX2, we found that SOX2 expressing tumors more often displayed a down-regulated expression of CDX2. In addition, SOX2 expressing tumors with a down-regulated CDX2 expression had a worse patient prognosis compared to those with retained CDX2 expression.ConclusionsOur results indicate that SOX2 expression induces a cellular stem cell state in human CRC with a decreased expression of CDX2. Furthermore, a down-regulated expression of CDX2 results in a poor patient prognosis in CRC and at least part of the prognostic importance of SOX2 is mediated through CDX2 down-regulation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2509-5) contains supplementary material, which is available to authorized users.

show abstract

The prognostic value of the stem-like group in colorectal cancer using a panel of immunohistochemistry markers

Cited by 15 publications

References 30 publications

Immune Contexture, Immunoscore, and Malignant Cell Molecular Subgroups for Prognostic and Theranostic Classifications of Cancers

Immune Contexture, Immunoscore, and Malignant Cell Molecular Subgroups for Prognostic and Theranostic Classifications of Cancers

Challenging the Cancer Molecular Stratification Dogma: Intratumoral Heterogeneity Undermines Consensus Molecular Subtypes and Potential Diagnostic Value in Colorectal Cancer

SOX2 expression is associated with a cancer stem cell state and down-regulation of CDX2 in colorectal cancer

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