Mapping spatial heterogeneity in the tumor microenvironment: a new era for digital pathology

Heindl, Andreas; Nawaz, Sidra; Yuan, Yinyin

doi:10.1038/labinvest.2014.155

Cited by 179 publications

(141 citation statements)

References 59 publications

(86 reference statements)

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“…New methods exists to map the spatial and morphological patterns of cancer and normal cells and can contribute to a more comprehensive understanding of the highly heterogeneous tumor microenvironment. 11 The following prerequisites are necessary for the analysis of the distribution pattern of inflammatory cells. First, digital slide scanners enable the acquisition of whole tissue images for analyzing the distribution pattern of a representative amount of cells.…”

Section: Introductionmentioning

confidence: 99%

“…Additional imaging analysis software is needed which can identify both tissue structures and individual cells and is able to compute cell-to-cell distances. 11,12 Therefore, in the present study we set out to explore whether not only the mere number of TIL in anal cancer biopsies, but also the proximity of individual cell types might have an influence on the outcome of the patients. We used double staining methods to study the interaction of FoxP3 + cells to CD8 + , CD1a + and CD20 + cells and compared the measured cell-to-cell distances with computer simulation-predicted distances.…”

Section: Introductionmentioning

confidence: 99%

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Cell-to-cell distances between tumor-infiltrating inflammatory cells have the potential to distinguish functionally active from suppressed inflammatory cells

et al. 2016

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Beyond their mere presence, the distribution pattern of inflammatory cells is of special interest. Our hypothesis was that random distribution may be a clear indicator of being non-functional as a consequence of lack of interaction. Here, we have assessed the implication of cell-to-cell distances among inflammatory cells in anal squamous cell carcinoma and a possible association with survival data. Thirtyeight patients suffering from anal carcinoma were studied using tissue microarrays, double staining immunohistochemistry, whole slide scanning and image analysis software. Therapy consisted of concurrent radiochemotherapy. Numbers of stromal and intraepithelial tumor-infiltrating inflammatory cells (TIC) and the distances between cells were quantified. Double-staining of FoxP3 + cells with either CD8 + , CD1a + or CD20 + cells was performed. Measured cell-to-cell distances were compared to computer simulated cell-to-cell distances leading to the assumption of non-randomly distributed and therefore functional immune cells. Intraepithelial CD1a + and CD20 + cells were randomly distributed and therefore regarded as non-functional. In contrary, stromal CD20 + cells had a non-random distribution pattern. A non-random distance between CD20 + and FoxP3 + cells was associated with a clearly unfavorable outcome. Measured distances between FoxP3 + cells were distinctly shorter than expected and indicate a functional active state of the regulatory T cells (Treg). Analysis of cell-to-cell distances between TIC has the potential to distinguish between suppressed non-functional and functionally active inflammatory cells. We conclude that in this tumor model most of the CD1a + cells are non-functional as are the intraepithelial CD20 + cells, while stromal CD20 + cells and FoxP3 + cells are functional cells.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cell-to-cell distances between tumor-infiltrating inflammatory cells have the potential to distinguish functionally active from suppressed inflammatory cells

et al. 2016

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“…Accordingly, the intratumoral diversity of vascular phenotypes is an important characteristic now recognized to affect antiangiogenic treatment, and has been intensively investigated in preclinical and clinical studies 18, 19, 20, 21, 22, 23. As an extension of these efforts, this study assessed region‐ and time‐dependent changes in TP and BV in MRI with dual injection of intravascular and extracellular fluid CAs.…”

Section: Discussionmentioning

confidence: 99%

Spatiotemporal heterogeneity of tumor vasculature during tumor growth and antiangiogenic treatment: MRI assessment using permeability and blood volume parameters

et al. 2018

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Tumor heterogeneity is an important concept when assessing intratumoral variety in vascular phenotypes and responses to antiangiogenic treatment. This study explored spatiotemporal heterogeneity of vascular alterations in C6 glioma mice during tumor growth and antiangiogenic treatment on serial MR examinations (days 0, 4, and 7 from initiation of vehicle or multireceptor tyrosine kinase inhibitor administration). Transvascular permeability (TP) was quantified on dynamic‐contrast‐enhanced MRI (DCE‐MRI) using extravascular extracellular agent (Gd‐DOTA); blood volume (BV) was estimated using intravascular T2 agent (SPION). With regard to region‐dependent variability in vascular phenotypes, the control group demonstrated higher TP in the tumor center than in the periphery, and greater BV in the tumor periphery than in the center. This distribution pattern became more apparent with tumor growth. Antiangiogenic treatment effect was regionally heterogeneous: in the tumor center, treatment significantly suppressed the increase in TP and decrease in BV (ie, typical temporal change in the control group); in the tumor periphery, treatment‐induced vascular alterations were insignificant and BV remained high. On histopathological examination, the control group showed greater CD31, VEGFR2, Ki67, and NG2 expression in the tumor periphery than in the center. After treatment, CD31 and Ki67 expression was significantly suppressed only in the tumor center, whereas VEGFR2 and α‐caspase 3 expression was decreased and NG2 expression was increased in the entire tumor. These results demonstrate that MRI can reliably depict spatial heterogeneity in tumor vascular phenotypes and antiangiogenic treatment effects. Preserved angiogenic activity (high BV on MRI and high CD31) and proliferation (high Ki67) in the tumor periphery after treatment may provide insights into the mechanism of tumor resistance to antiangiogenic treatment.

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“…31,32 Tumor microenvironment has sustainable impacts on tumor cell proliferation, invasion, and metastasis, and ultimately, it leads to morphological changes in histopathology images. 33 For example, immune cell infiltration within tumor stroma has distinct prognosis, 34 lymphovascular invasion is an adverse prognostic factor for BC, 35 and cancer-associated fibroblasts (CAFs) promote BC progress by inducing epithelial-to-mesenchymal transition. 36 Therefore, an improved comprehensive prognostic system should take account of the malignant epithelium features and the tumor microenvironment features.…”

Section: Routine Prognostic Prediction Based On Hande Histopathology Immentioning

confidence: 99%

Computer-aided prognosis on breast cancer with hematoxylin and eosin histopathology images: A review

Chen

et al. 2017

Tumour Biol.

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With the advance of digital pathology, image analysis has begun to show its advantages in information analysis of hematoxylin and eosin histopathology images. Generally, histological features in hematoxylin and eosin images are measured to evaluate tumor grade and prognosis for breast cancer. This review summarized recent works in image analysis of hematoxylin and eosin histopathology images for breast cancer prognosis. First, prognostic factors for breast cancer based on hematoxylin and eosin histopathology images were summarized. Then, usual procedures of image analysis for breast cancer prognosis were systematically reviewed, including image acquisition, image preprocessing, image detection and segmentation, and feature extraction. Finally, the prognostic value of image features and image feature–based prognostic models was evaluated. Moreover, we discussed the issues of current analysis, and some directions for future research.

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Mapping spatial heterogeneity in the tumor microenvironment: a new era for digital pathology

Cited by 179 publications

References 59 publications

Cell-to-cell distances between tumor-infiltrating inflammatory cells have the potential to distinguish functionally active from suppressed inflammatory cells

Cell-to-cell distances between tumor-infiltrating inflammatory cells have the potential to distinguish functionally active from suppressed inflammatory cells

Spatiotemporal heterogeneity of tumor vasculature during tumor growth and antiangiogenic treatment: MRI assessment using permeability and blood volume parameters

Computer-aided prognosis on breast cancer with hematoxylin and eosin histopathology images: A review

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