Cancer Letters

Cancer Letters

Volume 392, 28 April 2017, Pages 83-93
Cancer Letters

Mini-review
Crosstalk between stromal cells and cancer cells in pancreatic cancer: New insights into stromal biology

https://doi.org/10.1016/j.canlet.2017.01.041Get rights and content

Highlights

  • Pancreatic stroma is far more complex than a “passive bystander” in the carcinogenesis and development of pancreatic cancer.

  • The massive pancreatic cellular components play pivotal regulating roles in stroma biology.

  • The crosstalk between stromal cells and pancreatic cancer cells provides prognostic value and therapeutic target.

Abstract

Pancreatic cancer (PC) remains one of the most lethal malignancies worldwide. Increasing evidence has confirmed the pivotal role of stromal components in the regulation of carcinogenesis, invasion, metastasis, and therapeutic resistance in PC. Interaction between neoplastic cells and stromal cells builds a specific microenvironment, which further modulates the malignant properties of cancer cells. Instead of being a “passive bystander”, stroma may play a role as a “partner in crime” in PC. However, the role of stromal components in PC is complex and requires further investigation. In this article, we review recent advances regarding the regulatory roles and mechanisms of stroma biology, especially the cellular components such as pancreatic stellate cells, macrophages, neutrophils, adipocytes, epithelial cells, pericytes, mast cells, and lymphocytes, in PC. Crosstalk between stromal cells and cancer cells is thoroughly investigated. We also review the prognostic value and molecular therapeutic targets of stroma in PC. This review may help us further understand the molecular mechanisms of stromal biology and its role in PC development and therapeutic resistance. Moreover, targeting stroma components may provide new therapeutic strategies for this stubborn disease.

Introduction

Pancreatic ductal adenocarcinoma (PDAC, hereafter referred to as pancreatic cancer [PC]) remains the most lethal malignant tumor worldwide; an estimated 53,070 patients will be diagnosed with PC in 2016, while an estimated 41,780 patients died at the same time, and this malignant disease is predicted to be the second leading cause of cancer death by 2030 [1], [2]. Despite inspiring advancements in our understanding of the biology of PC, improvements in surgical skills, and new chemotherapeutic agents for neoadjuvant and adjuvant therapy in patients with PC, the long-term survival did not show significant improvement during the last two decades. Radical resection with clean resection margin (R0 resection) offers the best and the only curative treatment; however, when first diagnosed 80–85% of patients present with metastatic or locally advanced disease that is unresectable [3], [4]. Even for patients who undergo resection the prognosis remains poor because of the high rate of local recurrence and/or distant metastasis. Resistance to chemotherapy and radiation is another important reason for the poor prognosis of PC [5]. There are few effective treatments that can extend the overall survival of patients with PC. New strategies to explore the mechanisms of carcinogenesis, proliferation, metastasis, and therapeutic resistance of PC are urgently needed [6], [7].

An intense stromal desmoplastic reaction surrounding the cancer cells is the typical histological hallmark feature in PC [8], [9], [10]. This desmoplastic stromal tissue occupies approximately 80% of the total cancer nodule [10]. The stromal components consist of pancreatic stellate cells (PSCs), activated fibroblasts, macrophages, infiltrating immune cells, endothelial cells, and extracellular matrix (ECM), as well as a variety of enzymes and growth factors [9], [10]. Interaction between pancreatic cancer cells and stromal cells builds a specific microenvironment that further influences the malignant properties of cancer cells. The role of the pronounced stroma reaction in PC carcinogenesis, metastasis, and therapeutic resistance has been thoroughly investigated in previous studies [8], [10]. Although the stroma was thought to be a passive bystander for many years, several studies indicate that it is actually a “partner in crime” in PC [10], [11], [12]. However, some recent studies have demonstrated that targeting the stroma results in undifferentiated, aggressive pancreatic cancer, revealing a protective role of stroma in PC. Is stroma a “friend or foe” in PC [13]? This issue remains controversial and unclear, and the complex role of stroma in PC must be further investigated. In this article, we review recent advances regarding the regulatory roles and mechanisms of stromal components in PC, paying particular attention to the crosstalk between stromal cells and cancer cells. The prognostic value and molecular therapeutic targeting of stroma in PC are also reviewed.

Section snippets

Tumor microenvironment in PC

Tumor microenvironment (TME) is a complex and well-organized physical and biochemical system and the complicated biological interactions between tumor cells and the stroma play a pivotal role in tumor carcinogenesis, progression, metastasis, and therapeutic resistance [14], [15], [16]. Compared with normal tissue, the TME is characterized by altered functions of molecules in the extracellular matrix (ECM), the vascular and lymphatic networks, and abnormal phenotypes of stromal cells [17]. The

Crosstalk between stromal cells and cancer cells in PC

Stromal cells in PC are a group of heterogeneous connective tissue cells that fulfill distinct but complementary functions. They form the supportive structure in which the PC cells reside.

Prognostic value of stromal components in PC

The prognostic value of stroma in patients with PC has been evaluated in previous studies; however, the results remain controversial. In 2007, a study from Johns Hopkins Hospital revealed that patients whose peritumoral stromal fibroblasts expressed secreted protein acidic and rich in cysteine (SPARC) protein had a significantly worse prognosis than patients whose tumor stroma did not express SPARC, whereas expression of SPARC in PC cancer cells was not related to the prognosis of patients with

Stroma-targeted therapy in PC

Based on the understanding of stroma biology of PC and its important role in cancer progression and drug resistance, several modalities targeting stroma components have been thoroughly investigated. As mentioned previously, preclinical research using genetically engineered mouse models (GEMMs) revealed that stromal depletion by inhibition of the sonic hedgehog signal pathway resulted in increased intratumoral gemcitabine delivery and prolonged survival [144]. This inspiring result encouraged

Conclusion and future perspective

It is now well established that the desmoplastic reaction present in PC is not just a bystander response but is in fact a source of different cellular and acellular factors that promote tumor progression, immunosuppression, and metastasis. We have gained a lot of knowledge about the interactions between PC cells and stromal cells present in the TME of PC, especially the interactions between PC cells and macrophages, PSCs, neutrophils, adipocytes, epithelial cells, pericytes, mast cells, and

Acknowledgments

This work was supported by Natural Science Foundation of China (81302077), the China Postdoctoral Science Foundation (2013M531606), and the Shandong Provincial Natural Science Foundation, China (ZR2013HQ049).

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    These two authors contributed equally to this work.

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