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Tumor Microenvironment Participates in Metastasis of Pancreatic Cancer Bo Ren, Ming Cui, Gang Yang, Huanyu Wang, Mengyu Feng, Lei You*† and Yupei Zhao*†

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Tumor Microenvironment Participates in Metastasis of Pancreatic Cancer Bo Ren, Ming Cui, Gang Yang, Huanyu Wang, Mengyu Feng, Lei You*† and Yupei Zhao*† Ren et al. Molecular Cancer (2018) 17:108 https://doi.org/10.1186/s12943-018-0858-1 REVIEW Open Access Tumor microenvironment participates in metastasis of pancreatic cancer Bo Ren, Ming Cui, Gang Yang, Huanyu Wang, Mengyu Feng, Lei You*† and Yupei Zhao*† Abstract Pancreatic cancer is a deadly disease with high mortality due to difficulties in its early diagnosis and metastasis. The tumor microenvironment induced by interactions between pancreatic epithelial/cancer cells and stromal cells is critical for pancreatic cancer progression and has been implicated in the failure of chemotherapy, radiation therapy and immunotherapy. Microenvironment formation requires interactions between pancreatic cancer cells and stromal cells. Components of the pancreatic cancer microenvironment that contribute to desmoplasia and immunosuppression are associated with poor patient prognosis. These components can facilitate desmoplasia and immunosuppression in primary and metastatic sites or can promote metastasis by stimulating angiogenesis/lymphangiogenesis, epithelial- mesenchymal transition, invasion/migration, and pre-metastatic niche formation. Some molecules participate in both microenvironment formation and metastasis. In this review, we focus on the mechanisms of pancreatic cancer microenvironment formation and discuss how the pancreatic cancer microenvironment participates in metastasis, representing a potential target for combination therapy to enhance overall survival. Keywords: Pancreatic cancer, Tumor microenvironment, Desmoplasia, Immunosuppression, Metastasis Background requiring cellular elements that contribute to pancreatic Despite the significant advances in cancer research, pan- cancer microenvironment formation. creatic cancer is still a deadly disease. According to the Increasing interest has been focused on the tumor latest epidemiological data, a total of 55,440 patients microenvironment of pancreatic cancer. The pancreatic were newly diagnosed with pancreatic cancer, and cancer microenvironment consists of cancer cells, stro- 44,330 people died from the disease in the United States. mal cells and extracellular components. Stromal cells In contrast to other cancer types with continuous in- that contribute to pancreatic cancer progression are creases in survival, that of pancreatic cancer decreased mainly pancreatic stellate cells (PSCs), regulatory T cells slightly, and the disease is commonly diagnosed at an (Tregs), myeloid-derived suppressor cells (MDSCs), and advanced stage, leading to a 5-year survival rate of only tumor-associated macrophages (TAMs). These cells and 8% [1]. Among patients with pancreatic cancer, 90% cancer cells can secrete extracellular components, such carry a KRAS mutation, which is considered a driver as extracellular matrix (ECM), matrix metalloproteinase gene for pancreatic cancer progression, and 50–80% (MMP), growth factors, and transforming growth have inactivating mutations in TP53, CDKN2A, and factor-β (TGFβ), to maintain the microenvironment. Re- SMAD4 [2]. Pathological results have shown that the cent studies have demonstrated that the pancreatic can- most common type of pancreatic cancer is pancreatic cer microenvironment plays a critical role in PDAC ductal adenocarcinoma (PDAC). Pancreatic cancer is as- progression [3], revealing the relationship between the sociated with an extremely poor prognosis and high microenvironment and metastasis. There are two major mortality because it is usually diagnosed at advanced characteristics of the pancreatic cancer microenviron- stages with metastasized pancreatic cancer cells, ment: dense desmoplasia and extensive immunosuppres- sion [4]. These two features can facilitate pancreatic * Correspondence: [email protected]; [email protected] cancer cell proliferation, the evasion of immune surveil- †Lei You and Yupei Zhao contributed equally to this work. Department of General Surgery, Chinese Academy of Medical Sciences, lance via the direct inhibition of anti-tumor immunity or Peking Union Medical College, Peking Union Medical College Hospital, the induction of immunosuppressive cell proliferation Beijing 100023, People’s Republic of China © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Ren et al. Molecular Cancer (2018) 17:108 Page 2 of 15 and metastasis. Therefore, this review discusses pancre- studies of pancreatic cancer. The immune system during atic cancer microenvironment formation and the mecha- pancreatic cancer can not only suppress tumor develop- nisms by which the microenvironment participates in ment or progression by destroying cells with mutations metastasis to elucidate the relationship between the and prevent them from developing into tumor cells, but microenvironment and metastasis. it can also promote pancreatic cancer progression by es- tablishing favorable conditions for immunosuppression Characteristics of the pancreatic cancer and metastasis [17, 18]. The tumor infiltrating lympho- microenvironment cyte (TIL) population in pancreatic cancer shows clinical Desmoplasia correlates that higher proportions of CD4+, CD8+ and In pancreatic cancer, there is extensive fibrosis at primary dendritic cells (DCs) of TILs can improve the prognosis tumor sites, which is termed desmoplasia and docu- of affected patients with [19]. Among these immune mented in the pathology of PDAC. The clinical manifesta- cells, CD8+ T cells play an essential role in killing tumor tions of desmoplasia are overexpression of ECM proteins cells, and a greater number of cancer cell adjacent cyto- and extensive transformation of fibroblastic-type cells to a toxic T cells significantly correlates with survival [20]. myofibroblastic phenotype [5]. Desmoplasia is associated Normally, antigen-presenting cells (APCs), such as mac- with a poor prognosis by promoting the progression of rophages and DCs, process tumor antigens for display pancreatic cancer and resistance to chemotherapy [6]. on major histocompatibility complex (MHC) I mole- These cellular components can promote desmoplasia in cules, which activate subsequent CD8+ T cells to kill the pancreatic cancer microenvironment through the tumor cells via the granzyme, perforin, and first apop- secretion of certain molecules, such as TGFβ, fibroblast tosis signal (Fas)/FasL pathway. growth factor 2 (FGF2), and connective tissue growth Pancreatic cancer cells themselves are critical for im- factor (CTGF). Among these factors, TGFβ is notable for munosuppression by inhibiting CD8+ T cell activation its dual nature in cancer. It can prevent neoplastic cell and upregulating the existing regulatory immune cells. growth during pancreatic intraepithelial neoplasm-1 Pancreatic cancer has been shown to decrease its MHC (PanIN-1) and PanIN-2 while promoting growth during I expression to prevent recognition by CD8+ T cells for PanIN-3 due to the loss of SMAD4 and the canonical arm evasion [21]. Furthermore, Fas expression is downregu- of the TGFβ pathway [7, 8], and it interacts at many levels lated in pancreatic cancer cells, which leads to resistance with the RAS-RAF-ERK pathway [9]. Specimens from pa- to Fas-mediated apoptosis, and pancreatic cancer can in- tients have shown that ECM deposition in primary tumors duce apoptosis of CD8+ T cells by Fas/FasL counterat- is associated with a poor prognosis of patients with pan- tack [22]. Kaplan-Meier survival analysis demonstrated creatic cancer [10]. Desmoplasia can establish a hypoxic that high levels of Fas cytoplasmic expression in pancre- microenvironment by enhancing the functions of antian- atic cancer cells are significantly associated with a better giogenic factors. Hypoxia, which is caused by an insuffi- outcome of pancreatic cancer [23]. Immunosuppressive cient vasculature, is important for pancreatic cancer cytokines such as interleukin (IL)-10 and TGFβ are also aggressiveness, including metabolic reprogramming, in- secreted during pancreatic cancer to help fibrosis, im- hibition of apoptosis, sustained proliferation, treatment re- munosuppressive phenotype formation and recruit cells sistance, invasion and metastasis [11]. In contrast to other involved in immune evasion to overcome the anti-tumor solid tumors, pancreatic cancer cells can secrete antian- immunity [24–26]. Indoleamine 2,3-dioxygenase (IDO) giogenic factors, such as angiostatin, endostatin, and catalyzes the conversion from tryptophan to kynurenine, pigment epithelium-derived factors, into the hypovascular which leads to anergy of anti-tumor T cells and microenvironment, and ECM deposition can amplify enhances Treg function [27–29]. Moreover, high expres- endostatin production by cancer cells to enhance hypoxia sion of IDO in pancreatic cancer cells can mediate na- [12–14]. Recent studies have reported that desmoplasia ture killer (NK) cells dysfunction [30]. Commonly, components might be potential therapeutic targets of pan- Forkheadbox protein 3 (Foxp3), a transcription factor creatic cancer. For instance, hyaluronan degradation by considered a
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