title: Identification of a characteristic vascular belt zone in human colorectal cancer.
abstract: Intra-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.
  In 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.
  We 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.
authors.affiliation: Department of Medical Oncology and Internal Medicine VI, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg University, Heidelberg, Germany.|Institute of Pathology, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany.|Institute of Computer Assisted Clinical Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Jakob Nikolas
authors.identifier: http://orcid.org/0000-0002-3730-5348
authors.initials: JN
authors.lastname: Kather
authors.affiliation: Institute of Computer Assisted Clinical Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Frank Gerrit
authors.initials: FG
authors.lastname: Zöllner
authors.affiliation: Institute of Computer Assisted Clinical Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Lothar R
authors.initials: LR
authors.lastname: Schad
authors.affiliation: Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Susanne Maria
authors.identifier: http://orcid.org/0000-0002-6456-2681
authors.initials: SM
authors.lastname: Melchers
authors.affiliation: Department of Pathology, University Hospital Heidelberg, Heidelberg University, Heidelberg, Germany.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Sinn
authors.affiliation: Institute of Pathology, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Marx
authors.affiliation: Institute of Pathology, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Timo
authors.initials: T
authors.lastname: Gaiser
authors.affiliation: Institute of Pathology, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Cleo-Aron
authors.initials: CA
authors.lastname: Weis
mesh_terms: D001808:Blood Vessels / Q000503:physiopathology*; D015179:Colorectal Neoplasms / Q000098:blood supply* / Q000473:pathology; D006801:Humans; D007422:Intestines / Q000098:blood supply; D008113:Liver Neoplasms / Q000556:secondary; D055806:Microvessels / Q000503:physiopathology; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic