Mini-reviewCrosstalk between stromal cells and cancer cells in pancreatic cancer: New insights into stromal biology
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).
References (162)
- et al.
Pancreatic cancer
Lancet
(2011) - et al.
Pancreatic cancer stem cells: new insight into a stubborn disease
Cancer Lett.
(2015) - et al.
Hallmarks of cancer: the next generation
Cell
(2011) Pancreatic cancer-associated stroma production
Am. J. Surg.
(2007)- et al.
Pancreatic cancer stroma: friend or foe
Cancer Cell
(2014) - et al.
Microenvironmental regulation of therapeutic response in cancer
Trends Cell Biol.
(2015) - et al.
Key role of pancreatic stellate cells in pancreatic cancer
Cancer Lett.
(2016) - et al.
The myofibroblast: one function, multiple origins
Am. J. Pathol.
(2007) - et al.
The activated stroma index is a novel and independent prognostic marker in pancreatic ductal adenocarcinoma
Clin. Gastroenterol. Hepatol.
(2008) - et al.
Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma
Cancer Cell
(2012)
Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival
Cancer Cell
Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma
Cancer Cell
Identification, culture, and characterization of pancreatic stellate cells in rats and humans
Gastroenterology
Pancreatic stellate cells and pancreas cancer: current perspectives and future strategies
Eur. J. Cancer
Stars and stripes in pancreatic cancer: role of stellate cells and stroma in cancer progression
Front. Physiol.
CXCR2-dependent endothelial progenitor cell mobilization in pancreatic cancer growth
Transl. Oncol.
Tumor-derived granulocyte-macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer
Cancer Cell
Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a single-centre, open-label, dose-finding, non-randomised, phase 1b trial
Lancet Oncol.
Dissecting the tumor myeloid compartment reveals rare activating antigen-presenting cells critical for T cell immunity
Cancer Cell
Tumor-associated macrophages: from mechanisms to therapy
Immunity
Matrix metalloproteinases: regulators of the tumor microenvironment
Cell
Fibrogenesis in pancreatic cancer is a dynamic process regulated by macrophage-stellate cell interaction
Lab. Invest.
Mast cells and tumour angiogenesis: new insight from experimental carcinogenesis
Cancer Lett.
Cancer statistics, 2016
CA Cancer J. Clin.
Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States
Cancer Res.
Potentially curable pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline
J. Clin. Oncol.
Pancreatic adenocarcinoma
N. Engl. J. Med.
Pancreatic cancer biology and genetics from an evolutionary perspective
Nat. Rev. Cancer
The role of stroma in pancreatic cancer: diagnostic and therapeutic implications
Nat. Rev. Gastroenterol. Hepatol.
Pancreatic cancer stroma: understanding biology leads to new therapeutic strategies
World J. Gastroenterol.
Stromal biology and therapy in pancreatic cancer: a changing paradigm
Gut
Immunological hallmarks of stromal cells in the tumour microenvironment
Nat. Rev. Immunol.
Mucins in pancreatic cancer and its microenvironment
Nat. Rev. Gastroenterol. Hepatol.
The tumor microenvironment at a glance
J. Cell. Sci.
Molecular imaging of the tumor microenvironment
Adv. Drug Deliv. Rev.
Carcinoma-associated fibroblasts: orchestrating the composition of malignancy
Genes Dev.
Cancer-associated fibroblasts in pancreatic adenocarcinoma
Future Oncol.
The immune network in pancreatic cancer development and progression
Oncogene
The biology and function of fibroblasts in cancer
Nat. Rev. Cancer
Fibroblasts in cancer
Nat. Rev. Cancer
Fibroblast heterogeneity in the cancer wound
J. Exp. Med.
Adipocyte-derived fibroblasts promote tumor progression and contribute to the desmoplastic reaction in breast cancer
Cancer Res.
StellaTUM: current consensus and discussion on pancreatic stellate cell research
Gut
Evidence that fibroblasts derive from epithelium during tissue fibrosis
J. Clin. Invest.
Cancer: fibroblasts for all seasons
Nature
Hypoxia and the extracellular matrix: drivers of tumour metastasis
Nat. Rev. Cancer
Cancer-associated fibroblasts in pancreatic cancer are reprogrammed by tumor-induced alterations in genomic DNA methylation
Cancer Res.
The ever-expanding role of HIF in tumour and stromal biology
Nat. Cell Biol.
Pancreatic fibroblasts stimulate the motility of pancreatic cancer cells through IGF1/IGF1R signaling under hypoxia
PLoS ONE
Cancer-associated fibroblast-derived annexin A6+ extracellular vesicles support pancreatic cancer aggressiveness
J. Clin. Invest.
Cited by (106)
A comprehensive review on peptide-bearing biomaterials: From ex situ to in situ self-assembly
2024, Coordination Chemistry ReviewsLong non-coding RNA and the tumor microenvironment: Prospects for clinical applications in breast cancer
2023, Critical Reviews in Oncology/HematologyFibroblasts in pancreatic cancer: molecular and clinical perspectives
2023, Trends in Molecular MedicineDevelopment of a novel co-culture system using human pancreatic cancer cells and human iPSC-derived stellate cells to mimic the characteristics of pancreatic ductal adenocarcinoma in vitro
2023, Biochemical and Biophysical Research CommunicationsCancer plasticity: Investigating the causes for this agility
2023, Seminars in Cancer Biology
- 1
These two authors contributed equally to this work.