Stromal Features of the Primary Tumor Are Not Prognostic in Genetically Engineered Mice of Pancreatic Cancer.

Marie C Hasselluhn,Volker Ellenrieder,Lukas Klein,Albrecht Neesse,Philipp Ströbel,Sören M Buchholz,Patrick Maisonneuve,Melanie S Patzak

doi:10.3390/cells9010058

Marie C Hasselluhn, Volker Ellenrieder + Show 6 more

Open Access

https://doi.org/10.3390/cells9010058

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Journal: Cells	Publication Date: Dec 24, 2019
Citations: 10	License type: CC BY 4.0

Affiliation: European Institute of Oncology

Abstract

The KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre (KPC) mouse model is frequently employed for preclinical therapeutic testing, in particular in regard to antistromal therapies. Here, we investigate the prognostic implications of histopathological features that may guide preclinical trial design. Pancreatic tumor tissue from n = 46 KPC mice was quantitatively analyzed using immunohistochemistry and co-immunofluorescence for proliferation (Ki67), mitotic rate (phospho-Histone 3, PHH3), apoptosis (cleaved caspase-3, CC3), collagen content, secreted protein acidic and rich in cysteine (SPARC), hyaluronic acid (HA), and α-smooth muscle actin (α-SMA). Furthermore, mean vessel density (MVD), mean lumen area (MLA), grading, activated stroma index (ASI), and fibroblast-proliferation rate (α-SMA/Ki67) were assessed. Univariate analysis using the Kaplan–Meier estimator and Cox regression model for continuous variables did not show association between survival and any of the analyzed parameters. Spearman correlation demonstrated that desmoplasia was inversely correlated with differentiated tumor grade (ρ = −0.84). Ki67 and PHH3 synergized as proliferation markers (ρ = 0.54), while SPARC expression was positively correlated with HA content (ρ = 0.37). MVD and MLA were correlated with each other (ρ = 0.31), while MLA positively correlated with CC3 (ρ = 0.45). Additionally, increased MVD was correlated with increased fibroblast proliferation rate (α-SMA + Ki67; ρ = 0.36). Our pilot study provides evidence that individual histopathological parameters of the primary tumor of KPC mice are not associated with survival, and may hint at the importance of systemic tumor-related effects such as cachexia.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease that is projected to become the second leading cause of cancer-related death in the United States and Germany by 2030 [1,2]
In contrast to other epithelial cancers, PDAC is characterized by pronounced hypovascularity, and tumor vessels are compressed by ECM components, further decreasing PDAC perfusion
Ki67 and PHH3 were positively correlated as proliferation markers (% = 0.54), while Sparc expression was positively correlated with hyaluronan-binding protein (Habp) detection (% = 0.37)

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease that is projected to become the second leading cause of cancer-related death in the United States and Germany by 2030 [1,2]. PDAC represents the predominant form of pancreatic cancer and is genetically characterized by oncogenic. PDAC is marked by a robust desmoplastic response with the stromal compartment comprising up to 90% of the bulk tumor [3]. Inflammatory signaling cues within the tumor microenvironment, activated stellate cells (PSCs), and cancer-associated fibroblasts (CAFs) were shown to promote tumor progression and metastatic disease [5,6,7,8,9]. In contrast to other epithelial cancers, PDAC is characterized by pronounced hypovascularity, and tumor vessels are compressed by ECM components, further decreasing PDAC perfusion. It was hypothesized that the pronounced desmoplastic reaction may impede drug accumulation and response in PDAC by creating biophysical barriers, mediating chemoresistance in PDAC [10,11,12,13]

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