Stroma and pancreatic ductal adenocarcinoma: An interaction loop

Abstract

Pancreatic ductal adenocarcinom a (PDA) has two exceptional features. First, it is a highly lethal disease, with a median survival of less than 6 months and a 5-year survival rate less than 5%. Second, PDA tumor cells are surrounded by an extensive stroma, which accounts for up to 90% of the tumor volume. It is well recognized that stromal microenvironment can accelerate malignant transformation, tumor growth and progression. More importantly, the interaction loop between PDA and its stroma greatly contributes to tumor growth and progression. We propose that the extensive stroma of PDA is closely linked to its poor prognosis. An improved understanding of the mechanisms that contribute to pancreatic tumor growth and progression is therefore urgently needed. Targeting the stroma may thus provide novel prevention, earlier detection and therapeutic options to this deadly malignancy. Accordingly, in this review, we will summarize the mechanism of PDA stroma formation, the role of the stroma in tumor progression and therapy resistance and the potential of stroma-targeted therapeutics strategies.

Introduction

Pancreatic ductal adenocarcinoma (PDA) is a very aggressive and severe disease with the highest mortality rate worldwide, which is usually diagnosed at an advanced stage [1], [2]. Although these tumors represent less than 2% of cancer cases, they are the fourth leading cause of cancer-related death in the United States and other industrialized countries [3]; the median survival rate for those with clean microscopic surgical margins is approximately 2 years, with a 5-year survival of 15–20% [4].

One of the most prominent histological features of PDA is an extensive stroma that surrounds the tumor cells and accounts for up to 90% of the tumor volume (Fig. 1) [5]. There is a growing understanding of the contribution of the stromal microenvironment to the mechanisms responsible for malignant transformation and progression [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17]. The poor prognosis of PDA is highly correlated with the presence of an extensive matrix of stromal cells [18]. Additionally, mutations in proto-oncogenes and tumor suppressor genes [14] as well as distinctive epigenetic changes [19] are observed in both the tumor epithelium and the surrounding stromal cells. Whereas normal stroma can delay or prevent tumorigenesis, abnormal stromal components can promote tumor growth [20].

Because PDA is exceptional in both its lethality and the extent and compact of the stroma surrounding the tumor cells, researchers have wondered whether the stroma is at least partly responsible for its poor prognosis [21]. Recently, several studies have shown promising results by reducing the amount of stroma surrounding PDA tumors [18], [22], [23]. However, the pathophysiological mechanisms underlying the regulation and perpetuation of the stroma in PDA remain poorly understood [24], [25]. An improved understanding of the mechanisms that contribute to pancreatic tumor growth and progression is therefore urgently needed, and this knowledge will open new avenues for tumor prevention, earlier detection and improved therapy [26]. Accordingly, in this review, we will summarize the formation mechanism of PDA stroma, the role of the stroma in tumor progression, therapy resistance and the potential of stroma-targeted therapeutics in PDA.