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

ABSTRACT: Object: The aim of the present study was to investigate the clinicopathological characteristics and prognostic factors associated with sporadic colorectal cancer (CRC). We examined the clinicopathological findings and immunohistochemical expression of tumor prognostic markers at tumor budding sites to determine their predictive value for patient prognosis. Materials and Methods: Immunohistochemical examination was performed by tissue microarray (TMA) of specimens from 106 patients with CRC. On hematoxylin and eosin (H&E)-stained tumor tissue slides, a representative area of tumor budding at the invasive front was selected for the construction of a TMA. Immunostaining for matrix metalloproteinase-7 (MMP7), the laminin-5 (ln-5) ?2 chain and S100A4 was performed to determine the association between patient survival and these markers. Results: Clinicopathological variables were also assessed. Tumor location, histological type, degree of lymphatic invasion and vascular invasion, tumor stage, epithelial expression of S100A4, stromal cell expression of S100A4 and expression of the ln-5?2 chain were associated with an increased risk of mortality. Five factors were retained in the multivariate logistic regression analysis. Specifically, the tumor location, degree of lymphatic invasion and vascular invasion, tumor stage and stromal cell expression of S100A4 remained significant predictors of patient survival after controlling for the other variables. Conclusion: Vascular invasion and stromal expression of S100A4 in the tumor budding areas correlated with patient survival. Stromal immunostaining of S100A4 may be useful for identifying high-risk patients with advanced CRC.

SUBMITTER: Sugai T

PROVIDER: S-EPMC5535710 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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

Sugai Tamotsu T Yamada Noriyuki N Eizuka Makoto M Sugimoto Ryo R Uesugi Noriyuki N Osakabe Mitsumasa M Ishida Kazuyuki K Otsuka Kouki K Sasaki Akira A Matsumoto Takayuki T

Journal of Cancer 20170602 9

<b>Object</b>: The aim of the present study was to investigate the clinicopathological characteristics and prognostic factors associated with sporadic colorectal cancer (CRC). We examined the clinicopathological findings and immunohistochemical expression of tumor prognostic markers at tumor budding sites to determine their predictive value for patient prognosis. <b>Materials and Methods</b>: Immunohistochemical examination was performed by tissue microarray (TMA) of specimens from 106 patients ...[more]

PMID: 28775774

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Project description:BackgroundThe tumor microenvironment has a critical role in regulating cancer cell behavior. Tumors with high stromal content are associated with poor patient outcome. The tumor-stroma ratio (TSR) identifies colorectal cancers (CRC) with poor patient prognosis based on hematoxylin & eosin stained sections. The desmoplastic reaction consists to a great extent of cancer-associated fibroblasts (CAFs) of which different subtypes are known. The aim of this study is to investigate and quantify CAFs present in the tumor stroma of CRC stratified by the TSR to possibly add prognostic significance to the TSR.MethodsThe expression of established CAF markers was compared between stroma-low and stroma-high tumors using transcriptomic data of 71 stage I - III CRC. Based on literature, fibroblast and stromal markers were selected to perform multiplex immunofluorescent staining on formalin fixed, paraffin-embedded tumor sections of patients diagnosed with stage III colon cancer. Antibodies against the following markers were used: αSMA, PDGFR -β, FAP, FSP1 and the stromal markers CD45 and CD31 as reference. The markers were subsequently quantified in the stroma using the Vectra imaging microscope.ResultsThe transcriptomic data showed that all CAF markers except one were higher expressed in stroma-high compared to stroma-low tumors. Histologically, stroma-high tumors showed a decreased number of FSP1+/CD45+ cells and a trend of an increased expression of FAP compared to stroma-low tumors. FAP was higher expressed at the invasive part compared to the tumor center in both stroma-high and stroma-low tumors.ConclusionsThe increased expression of FAP at the invasive part and in stroma-high tumors might contribute to the invasive behavior of cancer cells. Future functional experiments should investigate the contribution of FAP to cancer cell invasion. Combining the quantity of the stroma as defined by the TSR with the activity level of CAFs using the expression of FAP may result in an expanded stroma-based tool for patient stratification.

Project description:ObjectiveVascular remodeling at the invasive tumor front (ITF) plays a critical role in progression and metastasis of triple negative breast cancer (TNBC). Therefore, there is a crucial need to characterize the vascular phenotype (i.e. changes in the structure and function of vasculature) of the ITF and tumor core (TC) in TNBC. This requires high-resolution, 3D structural and functional microvascular data that spans the ITF and TC (i.e. ∼4-5 mm from the tumor's edge). Since such data are often challenging to obtain with most conventional imaging approaches, we employed a unique "3D whole-tumor angiogenesis atlas" derived from orthotopic xenografts to characterize the vascular phenotype of the ITF and TC in TNBC.MethodsFirst, high-resolution (8 μm) computed tomography (CT) images of "whole-tumor" microvasculature were acquired from eight orthotopic TNBC xenografts, of which three tumors were excised at post-inoculation day 21 (i.e. early-stage) and five tumors were excised at post-inoculation day 35 (i.e. advanced-stage). These 3D morphological CT data were combined with soft tissue contrast from MRI as well as functional data generated in silico using image-based hemodynamic modeling to generate a multi-layered "angiogenesis atlas". Employing this atlas, blood vessels were first spatially stratified within the ITF (i.e. ≤1 mm from the tumor's edge) and TC (i.e. >1 mm from the tumor's edge) of each tumor xenograft. Then, a novel method was developed to visualize and characterize microvascular remodeling and perfusion changes in terms of distance from the tumor's edge.ResultsThe angiogenesis atlas enabled the 3D visualization of changes in tumor vessel growth patterns, morphology and perfusion within the ITF and TC. Early and advanced stage tumors demonstrated significant differences in terms of their edge-to-center distributions for vascular surface area density, vascular length density, intervessel distance and simulated perfusion density (p ≪ 0.01). Elevated vascular length density, vascular surface area density and perfusion density along the circumference of the ITF was suggestive of a preferential spatial pattern of angiogenic growth in this tumor cohort. Finally, we demonstrated the feasibility of differentiating the vascular phenotypes of ITF and TC in these TNBC xenografts.ConclusionsThe combination of a 3D angiogenesis atlas and image-based hemodynamic modeling heralds a new approach for characterizing the role of vascular remodeling in cancer and other diseases.

Dataset Information

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

Publications

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

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