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Article

Morphological Heterogeneity in Pancreatic Cancer Reflects Structural and Functional Divergence

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Department of Pathology, Oslo University Hospital, Rikshospitalet, 0424 Oslo, Norway
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Department of Pathology and Molecular Pathology, University Hospital Zürich, University of Zürich, 8091 Zürich, Switzerland
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Department of Pathology, Institute of Clinical Medicine, University of Oslo, 0316 Oslo, Norway
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Department of Data Science, Faculty of Science and Technology, Norwegian University of Life Sciences, 1430 Ås, Norway
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Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, 0316 Oslo, Norway
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Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Rikshospitalet, 0424 Oslo, Norway
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Department of Hepato-Pancreato-Biliary Surgery, Institute of Clinical Medicine, University of Oslo, 0316 Oslo, Norway
*
Author to whom correspondence should be addressed.
Academic Editor: Louis Buscail
Cancers 2021, 13(4), 895; https://doi.org/10.3390/cancers13040895
Received: 1 February 2021 / Revised: 12 February 2021 / Accepted: 16 February 2021 / Published: 20 February 2021
(This article belongs to the Section Tumor Microenvironment)
Pancreatic cancer has a poor prognosis, which is largely due to resistance to treatment. Tumor heterogeneity is a known cause for treatment failure and has been studied at the molecular level. Morphological heterogeneity is common but has not been investigated, despite the fact that pathology examination is an integral part of clinical diagnostics. This study assessed whether morphological heterogeneity reflects structural and functional diversity in key cancer biological processes. Using archival tissues from resected pancreatic cancer, we selected four common and distinct morphological phenotypes and demonstrated that these differed significantly for a panel of 26 structural and functional features of the cancer-cell and stromal compartments. The strong link between these features and morphological phenotypes allowed prediction of the latter based on the results for the panel of features. The findings of this study indicate that morphological heterogeneity reflects biological diversity and that its assessment may potentially provide clinically relevant information.
Inter- and intratumor heterogeneity is an important cause of treatment failure. In human pancreatic cancer (PC), heterogeneity has been investigated almost exclusively at the genomic and transcriptional level. Morphological heterogeneity, though prominent and potentially easily assessable in clinical practice, remains unexplored. This proof-of-concept study aims at demonstrating that morphological heterogeneity reflects structural and functional divergence. From the wide morphological spectrum of conventional PC, four common and distinctive patterns were investigated in 233 foci from 39 surgical specimens. Twenty-six features involved in key biological processes in PC were analyzed (immuno-)histochemically and morphometrically: cancer cell proliferation (Ki67) and migration (collagen fiber alignment, MMP14), cancer stem cells (CD44, CD133, ALDH1), amount, composition and spatial arrangement of extracellular matrix (epithelial proximity, total collagen, collagen I and III, fibronectin, hyaluronan), cancer-associated fibroblasts (density, αSMA), and cancer-stroma interactions (integrins α2, α5, α1; caveolin-1). All features differed significantly between at least two of the patterns. Stromal and cancer-cell-related features co-varied with morphology and allowed prediction of the morphological pattern. In conclusion, morphological heterogeneity in the cancer-cell and stromal compartments of PC correlates with structural and functional diversity. As such, histopathology has the potential to inform on the operationality of key biological processes in individual tumors. View Full-Text
Keywords: human pancreatic ductal adenocarcinoma; morphology; pathology; heterogeneity; stroma; extracellular matrix human pancreatic ductal adenocarcinoma; morphology; pathology; heterogeneity; stroma; extracellular matrix
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MDPI and ACS Style

Sántha, P.; Lenggenhager, D.; Finstadsveen, A.; Dorg, L.; Tøndel, K.; Amrutkar, M.; Gladhaug, I.P.; Verbeke, C. Morphological Heterogeneity in Pancreatic Cancer Reflects Structural and Functional Divergence. Cancers 2021, 13, 895. https://doi.org/10.3390/cancers13040895

AMA Style

Sántha P, Lenggenhager D, Finstadsveen A, Dorg L, Tøndel K, Amrutkar M, Gladhaug IP, Verbeke C. Morphological Heterogeneity in Pancreatic Cancer Reflects Structural and Functional Divergence. Cancers. 2021; 13(4):895. https://doi.org/10.3390/cancers13040895

Chicago/Turabian Style

Sántha, Petra, Daniela Lenggenhager, Anette Finstadsveen, Linda Dorg, Kristin Tøndel, Manoj Amrutkar, Ivar P. Gladhaug, and Caroline Verbeke. 2021. "Morphological Heterogeneity in Pancreatic Cancer Reflects Structural and Functional Divergence" Cancers 13, no. 4: 895. https://doi.org/10.3390/cancers13040895

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