Computational pathology: Exploring the spatial dimension of tumor ecology.

Tumors are evolving ecosystems where cancer subclones and the microenvironment interact. This is analogous to interaction dynamics between species in their natural habitats, which is a prime area of study in ecology. Spatial statistics are frequently used in ecological studies to infer complex relations including predator-prey, resource dependency and co-evolution. Recently, the emerging field of computational pathology has enabled high-throughput spatial analysis by using image processing to identify different cell types and their locations within histological tumor samples. We discuss how these data may be analyzed with spatial statistics used in ecology to reveal patterns and advance our understanding of ecological interactions occurring among cancer cells and their microenvironment.

[1]  Robert Axelrod,et al.  Ecological therapy for cancer: defining tumors using an ecosystem paradigm suggests new opportunities for novel cancer treatments. , 2008, Translational oncology.

[2]  C. Maley,et al.  Cancer is a disease of clonal evolution within the body1–3. This has profound clinical implications for neoplastic progression, cancer prevention and cancer therapy. Although the idea of cancer as an evolutionary problem , 2006 .

[3]  Arihiro Kano,et al.  Tumor cell secretion of soluble factor(s) for specific immunosuppression , 2015, Scientific Reports.

[4]  R. Poulin,et al.  Parasitism, commensalism, and mutualism: exploring the many shades of symbioses , 2008 .

[5]  Carissa A. Sanchez,et al.  Selectively Advantageous Mutations and Hitchhikers in Neoplasms , 2004, Cancer Research.

[6]  M. Speicher,et al.  Functional Network Pipeline Reveals Genetic Determinants Associated with in Situ Lymphocyte Proliferation and Survival of Cancer Patients , 2014, Science Translational Medicine.

[7]  H. Ross PARASITISM , 1912 .

[8]  Chen Zhou,et al.  A nationwide telepathology consultation and quality control program in China: implementation and result analysis , 2014, Diagnostic Pathology.

[9]  Susan Holmes,et al.  An Interactive Java Statistical Image Segmentation System: GemIdent. , 2009, Journal of statistical software.

[10]  G. G. Stokes "J." , 1890, The New Yale Book of Quotations.

[11]  J. Foidart,et al.  Whole Slide Quantification of Stromal Lymphatic Vessel Distribution and Peritumoral Lymphatic Vessel Density in Early Invasive Cervical Cancer: A Method Description , 2011, ISRN obstetrics and gynecology.

[12]  B. Vogelstein,et al.  p53 mutations in human cancers. , 1991, Science.

[13]  Douglas B. Evans,et al.  Cancer-associated stromal fibroblasts promote pancreatic tumor progression. , 2008, Cancer research.

[14]  J. Santora,et al.  Spatial association between hotspots of baleen whales and demographic patterns of Antarctic krill Euphausia superba suggests size-dependent predation , 2010 .

[15]  C. Janeway,et al.  T Cell-Mediated Immunity , 2001 .

[16]  P. Vaupel,et al.  Hypoxia in cancer: significance and impact on clinical outcome , 2007, Cancer and Metastasis Reviews.

[17]  Sidra Nawaz,et al.  Mapping spatial heterogeneity in the tumor microenvironment: a new era for digital pathology , 2015, Laboratory Investigation.

[18]  Alexander van Oudenaarden,et al.  Spatially resolved transcriptomics and beyond , 2014, Nature Reviews Genetics.

[19]  C. Breedis,et al.  The blood supply of neoplasms in the liver. , 1954, The American journal of pathology.

[20]  Andrew H. Beck,et al.  Systematic Analysis of Breast Cancer Morphology Uncovers Stromal Features Associated with Survival , 2011, Science Translational Medicine.

[21]  Benjamin Haibe-Kains,et al.  CD 4 + follicular helper T cell infiltration predicts breast cancer survival , 2013 .

[22]  K. Polyak,et al.  Tumorigenesis: it takes a village , 2015, Nature Reviews Cancer.

[23]  S. Astley,et al.  Breast screening interval and the characteristics of screen-detected cancers , 2015, Breast Cancer Research.

[24]  M. Junttila,et al.  Influence of tumour micro-environment heterogeneity on therapeutic response , 2013, Nature.

[25]  Stefan Michiels,et al.  Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[26]  Yinyin Yuan,et al.  Modelling the spatial heterogeneity and molecular correlates of lymphocytic infiltration in triple-negative breast cancer , 2015, Journal of The Royal Society Interface.

[27]  Robert J Gillies,et al.  Vascular measurements correlate with estrogen receptor status , 2014, BMC Cancer.

[28]  R. Gillies,et al.  Evolutionary dynamics of carcinogenesis and why targeted therapy does not work , 2012, Nature Reviews Cancer.

[29]  Yuan Zhang,et al.  Ovarian cancer-associated fibroblasts contribute to epithelial ovarian carcinoma metastasis by promoting angiogenesis, lymphangiogenesis and tumor cell invasion. , 2011, Cancer letters.

[30]  Benjamin Haibe-Kains,et al.  CD4⁺ follicular helper T cell infiltration predicts breast cancer survival. , 2013, The Journal of clinical investigation.

[31]  P. Fortina,et al.  The reverse Warburg effect: Aerobic glycolysis in cancer associated fibroblasts and the tumor stroma , 2009, Cell cycle.

[32]  C. Lawton,et al.  Tumor-Infiltrating CD8+ Lymphocytes Predict Clinical Outcome in Breast Cancer , 2012 .

[33]  Rafael Sirera,et al.  Angiogenesis in non-small cell lung cancer: the prognostic impact of neoangiogenesis and the cytokines VEGF and bFGF in tumours and blood. , 2006, Lung cancer.

[34]  Sidra Nawaz,et al.  Beyond immune density: critical role of spatial heterogeneity in estrogen receptor-negative breast cancer , 2015, Modern Pathology.

[35]  N. Restifo,et al.  Natural selection of tumor variants in the generation of “tumor escape” phenotypes , 2002, Nature Immunology.

[36]  W. Montevecchi,et al.  Distributional patterns of a marine bird and its prey: habitat selection based on prey and conspecific behaviour , 2003 .

[37]  Izhak Haviv,et al.  Co-evolution of tumor cells and their microenvironment. , 2009, Trends in genetics : TIG.

[38]  N. Mantel The detection of disease clustering and a generalized regression approach. , 1967, Cancer research.

[39]  T. Benton,et al.  Causes and consequences of animal dispersal strategies: relating individual behaviour to spatial dynamics , 2005, Biological reviews of the Cambridge Philosophical Society.

[40]  Mel Greaves,et al.  Evolutionary determinants of cancer. , 2015, Cancer discovery.

[41]  J. D. Toit,et al.  Large predators and their prey in a southern African savanna: a predator's size determines its prey size range , 2004 .

[42]  Jakob Nikolas Kather,et al.  Continuous representation of tumor microvessel density and detection of angiogenic hotspots in histological whole-slide images , 2015, Oncotarget.

[43]  S. Brooker,et al.  Bayesian spatial analysis and disease mapping: tools to enhance planning and implementation of a schistosomiasis control programme in Tanzania , 2006, Tropical medicine & international health : TM & IH.

[44]  Paolo Serafini,et al.  Myeloid suppressor cells in cancer: recruitment, phenotype, properties, and mechanisms of immune suppression. , 2006, Seminars in cancer biology.

[45]  F. Marincola,et al.  A signature of immune function genes associated with recurrence-free survival in breast cancer patients , 2012, Breast Cancer Research and Treatment.

[46]  H. Putter,et al.  The prognostic and predictive value of Tregs and tumor immune subtypes in postmenopausal, hormone receptor-positive breast cancer patients treated with adjuvant endocrine therapy: a Dutch TEAM study analysis , 2015, Breast Cancer Research and Treatment.

[47]  D. Patrick,et al.  The Characteristics of Wild Rat (Rattus spp.) Populations from an Inner-City Neighborhood with a Focus on Factors Critical to the Understanding of Rat-Associated Zoonoses , 2014, PloS one.

[48]  S. Gestl,et al.  Tumor cell heterogeneity maintained by cooperating subclones in Wnt-driven mammary cancers , 2014, Nature.

[49]  Dirk Brockmann,et al.  Spatial and Functional Heterogeneities Shape Collective Behavior of Tumor-Immune Networks , 2015, PLoS Comput. Biol..

[50]  Gyan Bhanot,et al.  Computerized Image-Based Detection and Grading of Lymphocytic Infiltration in HER2+ Breast Cancer Histopathology , 2010, IEEE Transactions on Biomedical Engineering.

[51]  Mark F. J. Steel,et al.  Non-Gaussian Bayesian Geostatistical Modeling , 2006 .

[52]  M. Schindl,et al.  Overexpression of hypoxia-inducible factor 1alpha is a marker for an unfavorable prognosis in early-stage invasive cervical cancer. , 2000, Cancer research.

[53]  C. S. Holling The components of prédation as revealed by a study of small-mammal prédation of the European pine sawfly. , 1959 .

[54]  Z. Trajanoski,et al.  Type, Density, and Location of Immune Cells Within Human Colorectal Tumors Predict Clinical Outcome , 2006, Science.

[55]  Yuan Qi,et al.  Molecular anatomy of breast cancer stroma and its prognostic value in estrogen receptor-positive and -negative cancers. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[56]  Aristotelis Tsirigos,et al.  Understanding the "lethal" drivers of tumor-stroma co-evolution , 2010, Cancer biology & therapy.

[57]  L. Wilkinson Immunity , 1891, The Lancet.

[58]  M. Washington,et al.  TGF-ß Signaling in Fibroblasts Modulates the Oncogenic Potential of Adjacent Epithelia , 2004, Science.

[59]  Dennis C. Sgroi,et al.  Stromal Fibroblasts Present in Invasive Human Breast Carcinomas Promote Tumor Growth and Angiogenesis through Elevated SDF-1/CXCL12 Secretion , 2005, Cell.

[60]  Andrew P Stubbs,et al.  Automated Selection of Hotspots (ASH): enhanced automated segmentation and adaptive step finding for Ki67 hotspot detection in adrenal cortical cancer , 2014, Diagnostic Pathology.

[61]  George Coukos,et al.  Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival , 2004, Nature Medicine.

[62]  C. Betsholtz,et al.  Paracrine signaling by platelet-derived growth factor-CC promotes tumor growth by recruitment of cancer-associated fibroblasts. , 2009, Cancer research.

[63]  Corrigendum: Interaction between RasV12 and scribbled clones induces tumour growth and invasion , 2017, Nature.

[64]  M. Fortin,et al.  Spatial Analysis: A Guide for Ecologists 1st edition , 2005 .

[65]  Fei Xing,et al.  Cancer associated fibroblasts (CAFs) in tumor microenvironment. , 2010, Frontiers in bioscience.

[66]  M. Archetti,et al.  Heterogeneity for IGF-II production maintained by public goods dynamics in neuroendocrine pancreatic cancer , 2015, Proceedings of the National Academy of Sciences.

[67]  J. Bosch,et al.  Determinants of Spatial Distribution in a Bee Community: Nesting Resources, Flower Resources, and Body Size , 2014, PloS one.

[68]  D. Doak,et al.  Abstracts, Reviews, and Meetings , 2011, Ecological Restoration.

[69]  David Basanta,et al.  Exploiting ecological principles to better understand cancer progression and treatment , 2013, Interface Focus.

[70]  Vilppu J Tuominen,et al.  ImmunoRatio: a publicly available web application for quantitative image analysis of estrogen receptor (ER), progesterone receptor (PR), and Ki-67 , 2010, Breast Cancer Research.

[71]  Peter Kareiva,et al.  Spatial ecology : the role of space in population dynamics and interspecific interactions , 1998 .

[72]  Pierre Gançarski,et al.  Combat or surveillance? Evaluation of the heterogeneous inflammatory breast cancer microenvironment , 2013, The Journal of pathology.

[73]  Z. Trajanoski,et al.  Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. , 2013, Immunity.

[74]  P. Allavena,et al.  Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. , 2002, Trends in immunology.

[75]  T. Bailey Spatial Analysis: A Guide for Ecologists , 2006 .

[76]  M. Morisita Measuring of dispersion of individuals and analysis of the distributional patterns. , 1961 .

[77]  Carlo C. Maley,et al.  An ecological measure of immune-cancer colocalization as a prognostic factor for breast cancer , 2015, Breast Cancer Research.

[78]  G. Hu,et al.  Epithelial-mesenchymal transition induced by growth suppressor p12CDK2-AP1 promotes tumor cell local invasion but suppresses distant colony growth. , 2008, Cancer research.

[79]  J. M. Nicholson,et al.  Is carcinogenesis a form of speciation? , 2011, Cell cycle.

[80]  R. Nesse,et al.  Evolutionary foundations for cancer biology , 2013, Evolutionary applications.

[81]  B. Roufogalis,et al.  Molecular and cellular regulators of cancer angiogenesis. , 2007, Current cancer drug targets.

[82]  Baishali Chaudhury,et al.  Heterogeneity in intratumoral regions with rapid gadolinium washout correlates with estrogen receptor status and nodal metastasis , 2015, Journal of magnetic resonance imaging : JMRI.

[83]  F. Markowetz,et al.  The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups , 2012, Nature.

[84]  B. Plancoulaine,et al.  An Original Approach for Quantification of Blood Vessels on the Whole Tumour Section , 2003, Analytical cellular pathology : the journal of the European Society for Analytical Cellular Pathology.

[85]  A generalised prey-predator type model of immunogenic cancer with the effect of immunotherapy , 2013 .

[86]  Carsten Denkert,et al.  Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[87]  S. Jalkanen,et al.  Type and location of tumor‐infiltrating macrophages and lymphatic vessels predict survival of colorectal cancer patients , 2012, International journal of cancer.

[88]  I. Ellis,et al.  The prognostic significance of B lymphocytes in invasive carcinoma of the breast , 2012, Breast Cancer Research and Treatment.

[89]  Axel Benner,et al.  Effects of infiltrating lymphocytes and estrogen receptor on gene expression and prognosis in breast cancer , 2009, Breast Cancer Research and Treatment.

[90]  F M Blows,et al.  Association between CD8+ T-cell infiltration and breast cancer survival in 12,439 patients. , 2014, Annals of oncology : official journal of the European Society for Medical Oncology.

[91]  Gurpreet Kaur,et al.  On Study of Immune Response to Tumor Cells in Prey-Predator System , 2014, International scholarly research notices.

[92]  Yousef Al-Kofahi,et al.  Improved Automatic Detection and Segmentation of Cell Nuclei in Histopathology Images , 2010, IEEE Transactions on Biomedical Engineering.

[93]  K. Pienta,et al.  Evolution of cooperation among tumor cells , 2006, Proceedings of the National Academy of Sciences.

[94]  B. Ripley The Second-Order Analysis of Stationary Point Processes , 1976 .

[95]  Carlo C. Maley,et al.  Clonal evolution in cancer , 2012, Nature.

[96]  Julien Verrax,et al.  Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. , 2008, The Journal of clinical investigation.

[97]  C. Wellbrock,et al.  Heterogeneous Tumor Subpopulations Cooperate to Drive Invasion , 2014, Cell reports.

[98]  F. Markowetz,et al.  Quantitative Image Analysis of Cellular Heterogeneity in Breast Tumors Complements Genomic Profiling , 2012, Science Translational Medicine.

[99]  Anant Madabhushi,et al.  A Boosted Bayesian Multiresolution Classifier for Prostate Cancer Detection From Digitized Needle Biopsies , 2012, IEEE Transactions on Biomedical Engineering.

[100]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

[101]  Klaus Zuberbühler,et al.  Cooperation and competition in two forest monkeys , 2004 .

[102]  A. Getis The Analysis of Spatial Association by Use of Distance Statistics , 2010 .

[103]  Erwin G. Van Meir Hypoxia-mediated selection of cells with diminished apoptotic potential to solid tumours. , 1996, Neurosurgery.

[104]  F.A.M. Bordonaba,et al.  Wild-Type KRAS Is Required for Panitumumab Efficacy in Patients With Metastatic Colorectal Cancer , 2009 .

[105]  D. DeAngelis,et al.  Effects of spatial grouping on the functional response of predators. , 1999, Theoretical population biology.

[106]  Jeff Gore,et al.  Turning ecology and evolution against cancer , 2014, Nature Reviews Cancer.

[107]  A. Marghoob,et al.  Histologic classification of tumor-infiltrating lymphocytes in primary cutaneous malignant melanoma. A study of interobserver agreement. , 2001, American journal of clinical pathology.

[108]  A. Ben-Baruch Inflammation-associated immune suppression in cancer: the roles played by cytokines, chemokines and additional mediators. , 2006, Seminars in cancer biology.

[109]  Robin L. Jones,et al.  Inference of tumor evolution during chemotherapy by computational modeling and in situ analysis of genetic and phenotypic cellular diversity. , 2014, Cell reports.

[110]  G. Sauter,et al.  Estrogen receptor alpha (ESR1) gene amplification is frequent in breast cancer , 2007, Nature Genetics.

[111]  J. Foidart,et al.  Improved computer-assisted analysis of the global lymphatic network in human cervical tissues , 2014, Modern Pathology.

[112]  Alissa M. Weaver,et al.  Tumor Morphology and Phenotypic Evolution Driven by Selective Pressure from the Microenvironment , 2006, Cell.

[113]  A. Ashworth,et al.  An integrative genomic and transcriptomic analysis reveals molecular pathways and networks regulated by copy number aberrations in basal-like, HER2 and luminal cancers , 2010, Breast Cancer Research and Treatment.

[114]  Alberto Mantovani,et al.  Macrophage plasticity and polarization: in vivo veritas. , 2012, The Journal of clinical investigation.

[115]  Robert A. Gatenby,et al.  Life history trade-offs in cancer evolution , 2013, Nature Reviews Cancer.