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CXCR4 in Tumor Epithelial Cells Mediates Desmoplastic Reaction In Published OnlineFirst June 30, 2020; DOI: 10.1158/0008-5472.CAN-19-2745 CANCER RESEARCH | GENOME AND EPIGENOME CXCR4 in Tumor Epithelial Cells Mediates Desmoplastic Reaction in Pancreatic Ductal Adenocarcinoma Toshihiro Morita1, Yuzo Kodama1,2, Masahiro Shiokawa1, Katsutoshi Kuriyama1, Saiko Marui1, Takeshi Kuwada1, Yuko Sogabe1, Tomoaki Matsumori1, Nobuyuki Kakiuchi1, Teruko Tomono1, Atsushi Mima1, Tatsuki Ueda1, Motoyuki Tsuda1, Yuki Yamauchi1, Yoshihiro Nishikawa1, Yojiro Sakuma1, Yuji Ota1, Takahisa Maruno1, Norimitsu Uza1, Takashi Nagasawa3, Tsutomu Chiba1,4, and Hiroshi Seno1 ABSTRACT ◥ Pancreatic ductal adenocarcinoma (PDAC) features abundant fibroblasts, and markedly less deposition of ECM. In vitro, KPC- stromal cells with an excessive extracellular matrix (ECM), termed Cxcr4-KO tumor cells exhibited higher proliferative and migratory the desmoplastic reaction. CXCR4 is a cytokine receptor for stromal activity than KPC-Cxcr4-WT tumor cells. Myofibroblasts induced cell-derived factor-1 (CXCL12) expressed in PDAC, but its invasion activity in KPC-Cxcr4-WT tumor cells, showing an epi- roles in PDAC and the characteristic desmoplastic reaction remain thelial–mesenchymal interaction, whereas KPC-Cxcr4-KO tumor unclear. Here, we generated a mouse model of PDAC with condi- cells were unaffected by myofibroblasts, suggesting their unique tional knockout of Cxcr4 (KPC-Cxcr4-KO) by crossing Cxcr4 nature. In human pancreatic cancer, undifferentiated carcinoma did flox mice with Pdx1-Cre;KrasLSL-G12D/þ;Trp53LSL-R172H/þ not express CXCR4 and exhibited histologic and IHC features (KPC-Cxcr4-WT) mice to assess the development of pancreatic similar to those in KPC-Cxcr4-KO mice. In summary, the intraepithelial neoplasia (PanIN) and pancreatic cancers. Tumor CXCL12/CXCR4 axis may play an important role in the desmo- cell characteristics of those two types were analyzed in vitro.In plastic reaction in PDAC, and loss of CXCR4 induces phenotype addition, CXCR4 expression in human pancreatic cancer specimens changes in undifferentiated carcinoma without a desmoplastic was evaluated by IHC staining. In KPC-Cxcr4-KO mice, the reaction. number and pathologic grade of PanIN lesions were reduced, but the frequency of pancreatic cancers did not differ from that in KPC- Significance: The current study uncovers CXCR4 as a key Cxcr4-WT mice. The pancreatic tumor phenotype in KPC-Cxcr4- regulator of desmoplastic reaction in PDAC and opens the way KO mice was significantly larger and undifferentiated, characterized for new therapeutic approaches to overcome the chemoresistance in by abundant vimentin-expressing cancer cells, significantly fewer patients with PDAC. Introduction with a ductal morphology, termed pancreatic intraepithelial neoplasia (PanIN; ref. 3). On the basis of findings from a pancreatic cancer Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal dis- mouse model, pancreatic cells bearing mutant Kras transform into ease. Despite progression in the development of therapies, the 5-year PanIN through acinar-to-ductal metaplasia, which eventually pro- survival rate of PDAC remains around 5% to 10% because of its gresses to PDAC. Several genetic alterations, transcriptional factors, resistance to anticancer drugs (1, 2). Therefore, novel therapeutic and chemokines are involved in the transformation (3, 4). targets of PDAC are urgently needed and clarifying the molecular A characteristic pathologic feature of PDAC is the abundance of mechanisms of this distinct disease can critically contribute to patient stromal tissues, including activated fibroblasts (myofibroblasts) and management. extracellular matrix (ECM), referred to as the desmoplastic reac- Pancreatic lesions are considered to progress step-by-step due to tion (5), which is considered to be a major contributor to chemore- multiple genetic alterations. PDAC arises from precancerous lesions sistance in PDAC. Although a number of previous works have identified pathways and fibroblast subtypes involved in the deposition of matrix in PDAC, the mechanism leading to the desmoplastic 1Department of Gastroenterology and Hepatology, Kyoto University Graduate response has not been fully elucidated yet (6–8). On the other hand, School of Medicine, Sakyo-ku, Kyoto, Japan. 2Department of Gastroenterology, a pancreatic cancer with few fibroblasts also exists. Undifferentiated 3 Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan. Laboratory carcinoma of the pancreas is a rare malignant epithelial neoplasm of Stem Cell Biology and Developmental Immunology, Graduate School of accounting for 0.8% to 5.7% of pancreatic cancer (9) that exhibits more Frontier Biosciences and Graduate School of Medicine, Osaka University, Osaka, Japan. 4Kansai Electric Power Hospital, Fukushima-ku, Osaka, Japan. aggressive clinical behavior and has a poorer prognosis than conven- tional PDAC (10). Its pathologic features include the lack of cell Note: Supplementary data for this article are available at Cancer Research differentiation, such as keratinization, glandular structure, or mucin Online (http://cancerres.aacrjournals.org/). production, and also fewer desmoplastic changes. The reasons for Corresponding Author: Yuzo Kodama, Kobe University Graduate School of these differences between conventional PDAC and undifferentiated Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017, Japan. carcinoma of the pancreas, however, are not well understood. Phone: 817-8382-6305; Fax: 817-8382-6309; E-mail; – [email protected] Stromal cell derived factor-1, now termed CXCL12, is a homeo- static chemokine that signals through its receptor CXCR4. CXCL12 Cancer Res 2020;80:1–13 and CXCR4 have a wide range of important roles in development, doi: 10.1158/0008-5472.CAN-19-2745 including hematopoiesis and immune system organization (11). Ó2020 American Association for Cancer Research. CXCR4 is a G-protein–coupled receptor encoded on chromosome AACRJournals.org | OF1 Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst June 30, 2020; DOI: 10.1158/0008-5472.CAN-19-2745 Morita et al. 2 (12) that promotes the downstream protein kinase B/mitogen- Histology activated protein kinases signaling pathway, leading to alterations in Tissues were sliced at 5 to 10 mm, fixed in 10% neutral phosphate- gene expression, actin polymerization, cell skeleton rearrangement, buffered formalin, embedded in paraffin, and stained with H&E. and cell migration (12). CXCR4 is expressed in many types of cancer cells, including PDAC, and is involved in growth, invasion, metastasis, IHC and prognosis (13–17). Stimulation of CXCL12, which is mainly The IHC study was performed according to the standard method. secreted by fibroblasts, increases the proliferation activity of cancer For mouse Cxcr4 staining, tissue sections were dephosphorylated by cells in vivo (18). Evaluation of tumors using Cxcr4 global knockout Lambda Phosphatase treatment (Santa Cruz Biotechnology) for 30 (KO) or conditional-KO mice, however, has not been reported. minutes at room temperature followed by antigen retrieval with In the current study, we investigated how CXCR4 in epithelial cells autoclave treatment (10 mmol/L citrate buffer, ph6). For human Cxcr4 affects the initiation and characteristics of PDAC using a mouse model staining, antigen retrieval was performed by autoclave (ph9 tris-EDTA with pancreas-specific Cxcr4 deletion. Here, we provide evidence that buffer) without dephosphorylation. Primary antibodies used in this CXCR4 plays a pivotal role in the desmoplastic changes in PDAC study are listed in Supplementary Table S2. Sections were incubated through cross-talk with CXCL12 from myofibroblasts. overnight with primary antibodies at 4C. The peroxidase reaction was carried out with Liquid DABþ Substrate Chromogen System (Dako). Materials and Methods Finally, slides were counterstained with hematoxylin (Wako). Human samples Alcian blue staining For IHC and hematoxylin and eosin (H&E) staining of human Alcian blue staining was performed as described previously (23). samples, surgically resected specimens were obtained from patients Briefly, slides were stained with pH 2.5 Alcian blue solution for 45 with PDAC or pancreatic undifferentiated carcinoma who had been minutes at room temperature and counterstained with nuclear fast red admitted to Kyoto University Hospital (Kyoto, Japan). solution (Sigma-Aldrich) for 10 minutes. Animals Sirius red staining All procedures were performed when mice were anesthetized by Sirius red staining was performed according to a general manual. isoflurane (Pfizer) and all efforts were made to minimize the number of Briefly, slides were stained in Picro-sirius red solution for 45 minutes at animals used and their suffering. Cxcr4 flox mice (19), Pdx1-Cre room temperature, then rinsed twice quickly with acetic acid solution G12D/þ R172H/þ mice (20), LSL-Kras mice (21), and LSL-Trp53 mice (22) followed by ethanol. were described previously. All mice were maintained on a mixed background. Quantitative RT-PCR Total RNA was extracted from the pancreatic tissues or cell lines Cell culture collected in RNA Later (Thermo Fisher Scientific) using an RNeasy Kit All tumor tissues were isolated by surgical dissection from KPC- (QIAGEN) according to the manufacturer's instructions. For com- Cxcr4 wild-type (WT) mice and KPC-Cxcr4-KO mice in 2017. Three plementary DNA synthesis, 1 mg of total RNA was reverse-transcribed primary culture cell lines were established from each
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