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Phenotyping of tumor-associated macrophages in colorectal cancer: Impact on single cell invasion (tumor budding) and clinicopathological outcome.

ABSTRACT: Tumor-associated macrophages (TAM) play a controversial role in epithelial-mesenchymal transition (EMT) and prognosis of colorectal cancer (CRC). In particular, the microlocalization, polarization and prognostic impact of TAM in the immediate environment of invading CRC cells has not yet been established. To address this clinically relevant question, intraepithelial (iCD68) and stromal macrophages (sCD68), M1-macrophages (iNOS), M2-macrophages (CD163), cytokeratin-positive cancer cells (tumor buds) and expression of the anti-phagocytic marker CD47 were investigated in primary tumors of 205 well-characterized CRC patients. Cell-to-cell contacts between tumor buds and TAM were detected using high-resolution digital scans. The composition of the tumor microenvironment was analyzed with clinicopathological and molecular features. High CD68 counts predicted long term overall survival independent of microlocalization (iCD68 p=0.0016; sCD68 p=0.03), pT, pN, pM and post-operative therapy. CD68 infiltration correlated with significantly less tumor budding (iCD68 p=0.0066; sCD68 p=0.0091) and absence of lymph node metastasis (sCD68 p=0.0286). Cell-to-cell contact of sCD68 and invading cancer cells was frequent and ameliorated the detrimental prognostic effect of the tumor budding phenotype. Subgroup analysis identified long-term survival with CD47 loss and predominance of CD163⁺ M2 macrophages (p = 0.0366). CD163⁺ macrophages represented 40% of the total population, and positively correlated with total CD68 macrophage numbers (r[CD68/CD163] = 0.32; p = 0.0001). Strong CD163 infiltration predicted lower tumor grade (p = 0.0026) and less lymph node metastasis (p = 0.0056). This study provides direct morphological evidence of an interaction between TAM and infiltrating cancer cells. The prognostic impact of TAM is modulated by phenotype, microlocalization and the expression of anti-phagocytic markers in CRC.

SUBMITTER: Koelzer VH

PROVIDER: S-EPMC4839334 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Phenotyping of tumor-associated macrophages in colorectal cancer: Impact on single cell invasion (tumor budding) and clinicopathological outcome.

Koelzer Viktor H VH Canonica Katharina K Dawson Heather H Sokol Lena L Karamitopoulou-Diamantis Eva E Lugli Alessandro A Zlobec Inti I

Oncoimmunology 20151109 4

Tumor-associated macrophages (TAM) play a controversial role in epithelial-mesenchymal transition (EMT) and prognosis of colorectal cancer (CRC). In particular, the microlocalization, polarization and prognostic impact of TAM in the immediate environment of invading CRC cells has not yet been established. To address this clinically relevant question, intraepithelial (iCD68) and stromal macrophages (sCD68), M1-macrophages (iNOS), M2-macrophages (CD163), cytokeratin-positive cancer cells (tumor bu ...[more]

PMID: 27141391

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Project description:BACKGROUND:Tumor budding, meaning a detachment of tumor cells at the invasion front of colorectal carcinoma (CRC) into single cells or clusters (<=5 tumor cells), has been shown to correlate to an inferior clinical outcome by several independent studies. Therefore, it has been discussed as a complementary prognostic factor to the TNM staging system, and it is already included in national guidelines as an additional prognostic parameter. However, its application by manual evaluation in routine pathology is hampered due to the use of several slightly different assessment systems, a time-consuming manual counting process and a high inter-observer variability. Hence, we established and validated an automatic image processing approach to reliably quantify tumor budding in immunohistochemically (IHC) stained sections of CRC samples. METHODS:This approach combines classical segmentation methods (like morphological operations) and machine learning techniques (k-means and hierarchical clustering, convolutional neural networks) to reliably detect tumor buds in colorectal carcinoma samples immunohistochemically stained for pan-cytokeratin. As a possible application, we tested it on whole-slide images as well as on tissue microarrays (TMA) from a clinically well-annotated CRC cohort. RESULTS:Our automatic tumor budding evaluation tool detected the absolute number of tumor buds per image with a very good correlation to the manually segmented ground truth (R2 value of 0.86). Furthermore the automatic evaluation of whole-slide images from 20 CRC-patients, we found that neither the detected number of tumor buds at the invasion front nor the number in hotspots was associated with the nodal status. However, the number of spatial clusters of tumor buds (budding hotspots) significantly correlated to the nodal status (p-value?=?0.003 for N0 vs. N1/N2). TMAs were not feasible for tumor budding evaluation, as the spatial relationship of tumor buds (especially hotspots) was not preserved. CONCLUSIONS:Automatic image processing is a feasible and valid assessment tool for tumor budding in CRC on whole-slide images. Interestingly, only the spatial clustering of the tumor buds in hotspots (and especially the number of hotspots) and not the absolute number of tumor buds showed a clinically relevant correlation with patient outcome in our data.

Project description:Background/purposeDespite high long-term survival rates in patients with Wilms tumor, there is a need to develop better prognostic biomarkers in order to maximize cure while avoiding treatment-associated morbidities. Tumor-associated macrophages have been recently associated with poorer prognosis and increased disease progression in a number of adult cancers. We investigated the relationship between macrophages and clinicopathological fators in this pediatric solid tumor.MethodsTissue microarray sections of 124 Wilms tumor cases obtained from the Cooperative Human Tissue Network were stained with CD68, a macrophage marker using standard immunohistochemical techniques and quantified using digital image processing techniques. Macrophage densities were correlated by tumor stage, and survival analyses were conducted with available clinical data. Immunohistochemistry was performed on 25 additional Wilms tumor cases obtained from the tumor bank at Columbia University Medical Center and correlated with presence of tumor microvascular invasion.ResultsMean macrophage count densities in stage IV tumors were significantly greater than densities in stage I and III tumors (p=.021, .036). Although the overall and disease-free survival did not differ between high and low macrophage presence groups across all stages, increased macrophage presence was associated with decreased disease-free survival in patients with stage II tumors (p=0.035). Increased macrophage presence may have also correlated with decreased disease-free survival in stage IV patients, but the sample size was too small to allow detection of this difference with significance (p=0.575). Increased macrophage presence was associated with tumor microvascular invasion (p=0.0004).ConclusionOur results suggest that macrophage recruitment may be associated with disease progression in Wilms tumor. Quantitation of macrophage presence may therefore be a useful adjunct in refining staging algorithms for patients with stage II Wilms tumor. Such data might be useful in the effort to reduce the risk of adverse effects associated with under- or overtreatment of this neoplasm.

Dataset Information

Phenotyping of tumor-associated macrophages in colorectal cancer: Impact on single cell invasion (tumor budding) and clinicopathological outcome.

Publications

Phenotyping of tumor-associated macrophages in colorectal cancer: Impact on single cell invasion (tumor budding) and clinicopathological outcome.

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