The Complex Intratumoral Heterogeneity of Colon Cancer Highlighted by Laser Microdissection

Buob, David; Fauvel, Harold; Buisine, Marie‐Pierre; Truant, Stéphanie; Mariette, C.; Porchet, Nicole; Wacrenier, Agnès; Copin, Marie‐Christine; Leteurtre, Emmanuelle

doi:10.1007/s10620-011-2023-1

Cited by 15 publications

(12 citation statements)

References 29 publications

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“…Navin and colleagues used comparative genomic hybridization techniques to demonstrate that multiple, genetically distinct clones were present within single breast cancer samples, and clonal subpopulations also varied between biopsies taken at different locations within the same tumor (Navin et al, 2010). Similar results have been observed in a wide-range of solid tumors and leukemia, suggesting that heterogeneity is a common trait among cancers (Götte et al, 2004; Campbell et al, 2010; Yachida et al, 2010; Anderson et al, 2011; Navin et al, 2011; Snuderl et al, 2011; Buob et al, 2012; Shah et al, 2012; Morrison et al, 2014). Next-generation sequencing and mathematical modeling have also provided unprecedented insight into the longitudinal sequence by which mutations are acquired as cancer cells clonally evolve (Fig.…”

Section: Intratumoral Heterogeneity and Clonal Evolutionsupporting

confidence: 82%

Zebrafish as a model to assess cancer heterogeneity, progression and relapse

Blackburn

Langenau

2014

Disease Models &Amp; Mechanisms

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Clonal evolution is the process by which genetic and epigenetic diversity is created within malignant tumor cells. This process culminates in a heterogeneous tumor, consisting of multiple subpopulations of cancer cells that often do not contain the same underlying mutations. Continuous selective pressure permits outgrowth of clones that harbor lesions that are capable of enhancing disease progression, including those that contribute to therapy resistance, metastasis and relapse. Clonal evolution and the resulting intratumoral heterogeneity pose a substantial challenge to biomarker identification, personalized cancer therapies and the discovery of underlying driver mutations in cancer. The purpose of this Review is to highlight the unique strengths of zebrafish cancer models in assessing the roles that intratumoral heterogeneity and clonal evolution play in cancer, including transgenesis, imaging technologies, high-throughput cell transplantation approaches and in vivo single-cell functional assays.

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Section: Intratumoral Heterogeneity and Clonal Evolutionsupporting

confidence: 82%

Zebrafish as a model to assess cancer heterogeneity, progression and relapse

Blackburn

Langenau

2014

Disease Models &Amp; Mechanisms

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“…Many factors could explain the differing results regarding the prognostic value of beta-catenin overexpression; e.g. intrinsic tumour heterogeneity [41], different immunohistochemical staining and visualization methods with varying degrees of sensitivity, and lack of standardization of what constitutes a “positive” or “negative” result. In many cases, nuclear beta-catenin expression is predominantly seen in the margin and not in the center of the tumour [42].…”

Section: Discussionmentioning

confidence: 99%

Associations of beta-catenin alterations and MSI screening status with expression of key cell cycle regulating proteins and survival from colorectal cancer

et al. 2013

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BackgroundDespite their pivotal roles in colorectal carcinogenesis, the interrelationship and prognostic significance of beta-catenin alterations and microsatellite instability (MSI) in colorectal cancer (CRC) needs to be further clarified. In this paper, we studied the associations between beta-catenin overexpression and MSI status with survival from CRC, and with expression of p21, p27, cyclin D1 and p53, in a large, prospective cohort study.MethodsImmunohistochemical MSI-screening status and expression of p21, p27 and p53 was assessed in tissue microarrays with tumours from 557 cases of incident CRC in the Malmö Diet and Cancer Study. Chi Square and Spearman’s correlation tests were used to explore the associations between beta-catenin expression, MSI status, clinicopathological characteristics and investigative parameters. Kaplan-Meier analysis and Cox proportional hazards modelling were used to assess the relationship between beta-catenin overexpression, MSI status and cancer specific survival (CSS).ResultsPositive MSI screening status was significantly associated with older age, female sex, proximal tumour location, non-metastatic disease, and poor differentiation, and inversely associated with beta-catenin overexpression. Beta-catenin overexpression was significantly associated with distal tumour location, low T-stage and well-differentiated tumours. Patients with MSI tumours had a significantly prolonged CSS in the whole cohort, and in stage III-IV disease, also in multivariable analysis, but not in stage I-II disease. Beta-catenin overexpression was associated with a favourable prognosis in the full cohort and in patients with stage III-IV disease. Neither MSI nor beta-catenin status were predictive for response to adjuvant chemotherapy in curatively treated stage III patients. P53 and p27 expression was positively associated with beta-catenin overexpression and inversely associated with MSI. Cyclin D1 expression was positively associated with MSI and beta-catenin overexpression, and p21 expression was positively associated with MSI but not beta-catenin overexpression.ConclusionsFindings from this large, prospective cohort study demonstrate that MSI screening status in colorectal cancer is an independent prognostic factor, but not in localized disease, and does not predict response to adjuvant chemotherapy. Beta-catenin overexpression was also associated with favourable outcome but not a treatment predictive factor. Associations of MSI and beta-catenin alterations with other investigative and clinicopathological factors were in line with the expected.Virtual slidesThe virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/8778585058652609

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“…Due to general limitations in biopsy size and punchable area due to the presence of bony trabeculae, the TMA was constructed as a single-punch per sample TMA. Whilst this may pose a problem in solid tumors, where tumor cell phenotype may differ significantly according to the localization in relation to the tumor center and tumor front [18], distribution and phenotype of the leukemic blasts within the individual marrow spaces in the biopsy should not differ significantly. Indeed, expression of CD47 was initially analyzed on whole tissue sections for establishment of the staining protocol b As induction therapy most patients underwent chemotherapeutic treatment with cytarabin and an antracycline, idarubicin or daunorubicin, respectively.…”

Section: Study Limitationsmentioning

confidence: 99%

CD47 protein expression in acute myeloid leukemia: A tissue microarray-based analysis

et al. 2015

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The Complex Intratumoral Heterogeneity of Colon Cancer Highlighted by Laser Microdissection

Abstract: We illustrated intratumoral heterogeneity of colon cancer using laser microdissection, in combination with immunohistochemical and genotypic tools. This intratumoral heterogeneity could represent a major issue in the search of prognostic biomarkers.

Cited by 15 publications

References 29 publications

Zebrafish as a model to assess cancer heterogeneity, progression and relapse

Zebrafish as a model to assess cancer heterogeneity, progression and relapse

Associations of beta-catenin alterations and MSI screening status with expression of key cell cycle regulating proteins and survival from colorectal cancer

CD47 protein expression in acute myeloid leukemia: A tissue microarray-based analysis

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