Identification of a characteristic vascular belt zone in human colorectal cancer.

Jakob Nikolas Kather,Timo Gaiser,Susanne Maria Melchers,Lothar R Schad,Cleo-Aron Weis,Frank Gerrit Zöllner,Hans-Peter Sinn,Alexander Marx

doi:10.1371/journal.pone.0171378

Abstract

Blood vessels in cancerIntra-tumoral blood vessels are of supreme importance for tumor growth, metastasis and therapy. Yet, little is known about spatial distribution patterns of these vessels. Most experimental or theoretical tumor models implicitly assume that blood vessels are equally abundant in different parts of the tumor, which has far-reaching implications for chemotherapy and tumor metabolism. In contrast, based on histological observations, we hypothesized that blood vessels follow specific spatial distribution patterns in colorectal cancer tissue. We developed and applied a novel computational approach to identify spatial patterns of angiogenesis in histological whole-slide images of human colorectal cancer.A characteristic spatial pattern of blood vessels in colorectal cancerIn 33 of 34 (97%) colorectal cancer primary tumors blood vessels were significantly aggregated in a sharply limited belt-like zone at the interface of tumor tissue to the intestinal lumen. In contrast, in 11 of 11 (100%) colorectal cancer liver metastases, a similar hypervascularized zone could be found at the boundary to surrounding liver tissue. Also, in an independent validation cohort, we found this vascular belt zone: 22 of 23 (96%) samples of primary tumors and 15 of 16 (94%) samples of liver metastases exhibited the above-mentioned spatial distribution.Summary and implicationsWe report consistent spatial patterns of tumor vascularization that may have far-reaching implications for models of drug distribution, tumor metabolism and tumor growth: luminal hypervascularization in colorectal cancer primary tumors is a previously overlooked feature of cancer tissue. In colorectal cancer liver metastases, we describe a corresponding pattern at the invasive margin. These findings add another puzzle piece to the complex concept of tumor heterogeneity.

Highlights

Spatial heterogeneity in solid tumorsHuman solid tumors have a high degree of spatial heterogeneity, both on a genetic [1] and on a tissue level [2, 3]
With the advent of digital pathology, microscopic objects in tumor tissue can be analyzed in a high-throughput manner in the entire spatial domain of a whole slide image (WSI) [2, 14]
We identified pathology reports that described a immunohistologically diagnosed microsatellite instability (MSI), a largely necrotic tumor or a tumor located in the appendix and omitted the corresponding samples

Summary

Introduction

Human solid tumors have a high degree of spatial heterogeneity, both on a genetic [1] and on a tissue level [2, 3] This tumor heterogeneity is reflected by non-uniform distribution of microscopic structures of interest within a tumor; for example blood vessels [4], proliferating tumor cells [5] or lymphocytes in primary tumors [6, 7] and metastases [8, 9]. Objects (such as blood vessels) and their features (e.g. size or shape) can be measured and subsequently visualized e.g. as a density map (heat map) Within these maps, one can appreciate the heterogeneity of the underlying data. We have recently proposed a new method to analyze blood vessels that is based on spatial statistics and identifies all hotspot areas that are unlikely to occur by chance [4]

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