Synergistic metalloproteinase-based remodeling of matrix by pancreatic tumor and stromal cells.

Hong Cao,Gina L Razidlo,Li Qiang,Mark A Mcniven,Jing Chen,Katherine M Johnson,Tobias Zech

doi:10.1371/journal.pone.0248111

Abstract

The process by which tumor cells mechanically invade through the surrounding stroma into peripheral tissues is an essential component of metastatic dissemination. Matrix metalloproteinase (MMP)-mediated extracellular matrix (ECM) degradation plays an important role in this invasive process. Defining the contribution and interaction between these MMPs during invasion remains a key interest in the development of targeted anti-metastatic therapies. In this study we have utilized multiple different stromal fibroblasts and tumor cells to define the relative contributions between cancer cells and stromal cells during MMP-dependent matrix remodeling and pancreatic (PDAC) tumor cell invasion. We find that tumor cells co-cultured with the conditioned medium from stromal fibroblasts exhibited a substantial increase in invadopodial-based matrix degradation and transwell invasion. This increase is dependent on pro-MMP2 expressed and secreted by stromal fibroblasts. Further, the pro-MMP2 from the stromal fibroblasts is activated by MT1-MMP expressed on the tumor cells. Depletion of MT1-MMP, the known activator of MMP2, in tumor cells largely blocked matrix remodeling, even in the presence of stromal cell medium. In summary, these findings implicate an important interplay between MT1-MMP from tumor cells and MMP2 from fibroblasts as a key component for ECM remodeling and invasion.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) is a lethal and highly metastatic cancer
Fibroblasts stimulate the invasive properties of pancreatic cancer cells As fibroblasts are known to promote invasive metastasis of various tumor types by a variety of processes, we tested if stromal cells might alter the ability of pancreatic cancer cells to degrade extracellular matrix components in vitro
BxPC3 PDAC cells were seeded on fluorescent gelatin-coated coverslips alone, with or without human pancreatic stellate cells, which are one source of cancer-associated fibroblasts (CAFs) in pancreatic tumors, as well as normal human or rat fibroblasts

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is a lethal and highly metastatic cancer. The high mortality rate for pancreatic cancer is largely due to the advanced stage at which the disease is diagnosed, resistance to therapies, and early metastasis [1,2,3]. Pancreatic tumors are exceptionally invasive and are believed to invade peripheral tissues via a combination of stromal remodeling and active migration that facilitates the intravasation of this tumor into the adjacent vasculature [4, 5]. This remodeling of the surrounding tumor environment is achieved in part through the secretion of a variety of different matrix metalloproteinases (MMPs).

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