論文 - 西原　広史

【大腸癌診療におけるprecision medicine】ゲノム解析を利用した大腸癌原発巣およびその肝転移巣に対するprecision medicine

川俣 太, Patch Ann-Marie, Nones Katia, 本間 重紀, 西原 広史, 神山 俊哉, 武冨 紹信, Leggett Barbara, Waddell Nicola, Whitehall Vicki

癌の臨床 （(株)篠原出版新社）  65 （ 4 ） 373 - 382 2021年01月

ISSN  0021-4949

　概要を見る

ゲノム解析を利用して同一患者の大腸癌原発巣と肝転移巣を比較検討し、化学療法の治療経過や転移過程における時空間的なゲノム変異の解明を試みた。その結果、臨床的に「actionable」な大腸癌ドライバー遺伝子が大腸癌と転移巣間では異なり、原発巣の病理結果から再発・転移巣に対する化学療法を選択しても、再発・転移巣には化学療法が奏功しない可能性が考えられた。また、ドライバー遺伝子の相違は原発巣から転移巣における治療過程でのclonal evolutionによって引き起こされることから、治療経過における転移巣切除や肝生検、リキッドバイオプシーを積極的に行うことで、より正確な真の癌個別化医療が進んでいくものと示唆された。

Pulmonary metastasis secondary to abiraterone-resistant prostate cancer with homozygous deletions of BRCA2: First Japanese case.

Izawa M, Kosaka T, Nakamura K, Oba J, Hishida T, Hongo H, Mikami S, Nishihara H, Oya M

IJU case reports 4 （ 1 ） 14 - 17 2021年01月

査読有り

　概要を見る

Introduction: Most metastatic prostate cancers acquire the capacity for androgen-independent growth and become resistant to androgen deprivation therapy. A patient-focused treatment strategy is needed for aggressive castration-resistant prostate cancer. Case presentation: We report the case of a 62-year-old man who presented with prostatic adenocarcinoma who was treated by radiation and combined androgen blockade. After completion of first-line therapy, he was diagnosed with multiple metastatic castration-resistant prostate cancer in the lung. Second-line therapy with abiraterone acetate resulted in partial remission of the lung metastases. Thoracic surgery was performed to remove the single lung metastasis remaining. Next-generation sequencing of the specimens demonstrated homozygous loss of BRCA2. We note in this case a heterogeneous response to abiraterone acetate may be related to the somatic BRCA2 deletions. Conclusions: We present the first Japanese case of a metastatic abiraterone acetate-resistant castration-resistant prostate cancer accompanied by BRCA2 mutation.

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CDK12 and HER2 coamplification in two urothelial carcinomas with rapid and aggressive clinical progression.

Yoshinori Yanai, Takeo Kosaka, Kohei Nakamura, Eriko Aimono, Kazuhiro Matsumoto, Shinya Morita, Shuji Mikami, Hiroshi Nishihara, Mototsugu Oya

Cancer science 111 （ 12 ） 4652 - 4655 2020年12月

　概要を見る

Cyclin-dependent kinase 12 (CDK12), one of the key factors associated with DNA damage response pathways, is located on chromosome 17 proximal to Erb-B2 receptor tyrosine kinase 2 (ERBB2). In this report, CDK12 and ERBB2 coamplification was detected by targeted next-generation sequencing in two urothelial carcinomas. The staining intensity of the CDK12 and human epidermal growth factor receptor-2 proteins was associated with the prognosis of each urothelial carcinoma case. Our results suggest that CDK12 coamplification with ERBB2 might be associated with tumor aggressiveness and contribution to cancer pathogenesis. Therapies targeting CDK12 should be developed for these patients.

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CDK12andHER2coamplification in two urothelial carcinomas with rapid and aggressive clinical progression

Yoshinori Yanai, Takeo Kosaka, Kohei Nakamura, Eriko Aimono, Kazuhiro Matsumoto, Shinya Morita, Shuji Mikami, Hiroshi Nishihara, Mototsugu Oya

CANCER SCIENCE （WILEY）  111 （ 12 ） 4652 - 4655 2020年12月

ISSN  1347-9032

　概要を見る

Cyclin-dependent kinase 12 (CDK12), one of the key factors associated with DNA damage response pathways, is located on chromosome 17 proximal to Erb-B2 receptor tyrosine kinase 2 (ERBB2). In this report,CDK12andERBB2coamplification was detected by targeted next-generation sequencing in two urothelial carcinomas. The staining intensity of the CDK12 and human epidermal growth factor receptor-2 proteins was associated with the prognosis of each urothelial carcinoma case. Our results suggest thatCDK12coamplification withERBB2might be associated with tumor aggressiveness and contribution to cancer pathogenesis. Therapies targeting CDK12 should be developed for these patients.

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Association of Epstein–Barr virus with regression after withdrawal of immunosuppressive drugs and subsequent progression of iatrogenic immunodeficiency‐associated lymphoproliferative disorders in patients with autoimmune diseases

Katsuya Fujimoto, Kanako C. Hatanaka, Yutaka Hatanaka, Ikumi Kasahara, Satoshi Yamamoto, Takahiro Tsuji, Masanobu Nakata, Yasunari Takakuwa, Yoshihito Haseyama, Yumiko Oyamada, Masakatsu Yonezumi, Hiroaki Suzuki, Hajime Sakai, Hiroko Noguchi, Akio Mori, Hiroshi Nishihara, Takanori Teshima, Yoshihiro Matsuno

Hematological Oncology （Wiley）  38 （ 5 ） 799 - 807 2020年12月

ISSN  0278-0232

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Clinical implications of next-generation sequencing-based panel tests for malignant ovarian tumors.

Saotome K, Chiyoda T, Aimono E, Nakamura K, Tanishima S, Nohara S, Okada C, Hayashi H, Kuroda Y, Nomura H, Susumu N, Iwata T, Yamagami W, Kataoka F, Nishihara H, Aoki D

Cancer medicine （WILEY）  9 （ 20 ） 7407 - 7417 2020年10月

査読有り,  ISSN  2045-7634

　概要を見る

Precision medicine based on cancer genomics is being applied in clinical practice. However, patients do not always derive benefits from genomic testing. Here, we performed targeted amplicon exome sequencing-based panel tests, including 160 cancer-related genes (PleSSision-160), on 88 malignant ovarian tumors (high-grade serous carcinoma, 27; endometrioid carcinoma, 15; clear cell carcinoma, 30; mucinous carcinoma, 6; undifferentiated carcinoma, 4; and others, 6 (immature teratoma, 1; carcinosarcoma, 3; squamous cell carcinoma, 1; and mixed, 1)), to assess treatment strategies and useful biomarkers for malignant ovarian tumors. Overall, actionable gene variants were found in 90.9%, and druggable gene variants were found in 40.9% of the cases. ActionableBRCA1andBRCA2variants were found in 4.5% of each of the cases.ERBB2amplification was found in 33.3% of mucinous carcinoma cases. Druggable hypermutation/ultramutation (tumor mutation burden >= 10 SNVs/Mbp) was found in 7.4% of high-grade serous carcinoma, 46.7% of endometrioid carcinoma, 10% of clear cell carcinoma, 0% of mucinous carcinoma, 25% of undifferentiated carcinoma, and 33.3% of the other cancer cases. Copy number alterations were significantly higher in high-grade serous carcinoma (P < .005) than in other histologic subtypes; some clear cell carcinoma showed high copy number alterations that were correlated with advanced stage (P < .05) and worse survival (P < .01). A high count of copy number alteration was associated with worse survival in all malignant ovarian tumors (P < .05). Our study shows that targeted agents can be detected in approximately 40% of malignant ovarian tumors via multigene panel testing, and copy number alteration count can be a useful marker to help assess risks in malignant ovarian tumor patients.

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がん遺伝子パネル検査を受診した患者の全身状態の推移および遺伝子結果から、治療へ還元させるための検査実施時期に関する考察

今井 光穂, 持田 かおり, 藤倉 智花, 柳田 絵美衣, 山田 寛, 四十物 絵理子, 中村 康平, 林 秀幸, 植木 有紗, 西原 広史

日本癌学会総会記事 （(一社)日本癌学会）  79回   OJ7 - 3 2020年10月

査読有り,  ISSN  0546-0476

次世代シーケンサーを用いたゲノム解析による、ERBB2増幅症例での治療推奨におけるコピー数のカットオフ値の標準化について

中村 康平, 四十物 絵理子, 大場 純奈, 植木 有紗, 今井 光穂, 柳田 絵美衣, 山田 寛, 林 秀幸, 西原 広史

日本癌学会総会記事 （(一社)日本癌学会）  79回   OJ7 - 6 2020年10月

査読有り,  ISSN  0546-0476

Extramammary Paget's disease patient-derived xenografts harboring ERBB2 S310F mutation show sensitivity to HER2-targeted therapies.

Maeda T, Kitamura S, Nishihara H, Yanagi T

Oncogene 39 （ 36 ） 5867 - 5875 2020年09月

査読有り,  ISSN  0950-9232

　概要を見る

Although the prognosis of advanced extramammary Paget's disease (EMPD) is poor, there have been no preclinical research models for the development of novel therapeutics. This study aims to establish a preclinical research model for EMPD. We transplanted EMPD tissue into immunodeficient NOD/Scid mice. Histopathological and genetic analyses using a comprehensive cancer panel were performed. For in vivo preclinical treatments, trastuzumab, lapatinib, docetaxel, or eribulin were administered to patient-derived xenograft (PDX) models. Tissue transplanted from the EMPD patient was enlarged in NOD/Scid mice and was transplanted into further generations. Both the transplantation of PDX into nu/nu mice and the reanimation of the cryopreserved xenografted tumors in NOD/Scid mice were successful. We also established an EMPD-PDX-derived primary cell culture. Histopathologically, the xenografted tumors were positive for CK7, which was consistent with the patient's tumors. Genetically, the pathogenic mutation ERBB2 S310F was detected in the patient's tumors (primary intraepidermal lesion, metastatic lymph node) and was observed in the xenografted tumors even after continued passages. The xenografted tumors responded well to trastuzumab and lapatinib therapy. Also, cytotoxic agents (docetaxel and eribulin) were effective against the xenografted tumors. This PDX model (EMPD-PDX-H1) could be a powerful tool for the research and development of EMPD treatments.

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Clinical impact of a cancer genomic profiling test using an in-house comprehensive targeted sequencing system.

Hayashi H, Tanishima S, Fujii K, Mori R, Okada C, Yanagita E, Shibata Y, Matsuoka R, Amano T, Yamada T, Yabe I, Kinoshita I, Komatsu Y, Dosaka-Akita H, Nishihara H

Cancer science 111 （ 10 ） 3926 - 3937 2020年08月

査読有り,  ISSN  1347-9032

　概要を見る

Precision medicine is a promising strategy for cancer treatment. In this study, we developed an in-house clinical sequencing system to perform a comprehensive cancer genomic profiling test as a clinical examination and analyzed the utility of this system. Genomic DNA was extracted from tumor tissues and peripheral blood cells collected from 161 patients with different stages and types of cancer. A comprehensive targeted amplicon exome sequencing for 160 cancer-related genes was performed using next-generation sequencing (NGS). The sequencing data were analyzed using an original bioinformatics pipeline, and multiple cancer-specific gene alterations were identified. The success rate of our test was 99% (160/161), while re-biopsy was required for 24% (39/161) of the cases. Potentially actionable and actionable gene alterations were detected in 91% (145/160) and 46% (73/160) of the patients, respectively. The actionable gene alterations were frequently detected in PIK3CA (9%), ERBB2 (8%), and EGFR (4%). High tumor mutation burden (TMB) (≥10 mut/Mb) was observed in 12% (19/160) of the patients. The secondary findings in germline variants considered to be associated with hereditary tumors were detected in 9% (15/160) of the patients. Seventeen patients (11%, 17/160) were treated with genotype-matched therapeutic agents, and the response rate was 47% (8/17). The median turnaround time for physicians was 20 days, and the median survival time after the initial visit was 8.7 months. The results of the present study prove the feasibility of implementing in-house clinical sequencing as a promising laboratory examination technique for precision cancer medicine.

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A phase 2 basket trial of combination therapy with trastuzumab and pertuzumab in patients with solid cancers harboring human epidermal growth factor receptor 2 amplification (JUPITER trial).

Takahashi K, Ishibashi E, Kubo T, Harada Y, Hayashi H, Kano M, Shimizu Y, Shirota H, Mori Y, Muto M, Ishioka C, Dosaka-Akita H, Matsubara H, Nishihara H, Sueoka-Aragane N, Toyooka S, Hirakawa A, Tateishi U, Miyake S, Ikeda S

Medicine 99 （ 32 ） e21457 2020年08月

査読有り,  ISSN  0025-7974

　概要を見る

INTRODUCTION: Human epidermal growth factor receptor 2 (HER2) gene amplification and mutations have emerged as oncogenic drivers and therapeutic targets not limited to breast and gastric cancers, but also in a variety of cancers. However, even if an actionable gene alteration is found, the incidence of HER2 amplification in these cancers is less than 5%. It is too difficult to conduct a conventional randomized, controlled trial in a rare fraction. Therefore, we have designed a organ-agnostic basket study, which covers a variety of solid cancers harboring HER2 amplification, in 1 study protocol. METHODS/DESIGN: This trial is a multicenter, single-arm, basket phase 2 study in Japan. Patients with solid cancers harboring HER2 amplification that have progressed with standard treatment, or rare cancers for which there is no standard treatment, will be eligible. Target cancers include bile duct, urothelial, uterine, ovarian, and other solid cancers where HER2 amplification is detected by comprehensive genomic profiling using next-generation sequencing technology. A total of 38 patients will be treated with combination therapy with trastuzumab and pertuzumab every 3 weeks until disease progression, unmanageable toxicity, death, or patient refusal. The primary endpoint is the objective response rate, and secondary endpoints are progression-free survival, overall survival, and duration of response. DISCUSSION: The aim of this trial is to evaluate the safety and efficacy of combination therapy with trastuzumab and pertuzumab in patients with locally advanced or metastatic, solid cancers harboring HER2 amplification. Instead of focusing on 1 organ type, our trial design uses a basket study focusing on HER2 amplification, regardless of the site or origin of the cancer. The results of our study will advance clinical and scientific knowledge concerning the treatment of locally advanced, rare solid cancers harboring HER2 amplification, using the combination of trastuzumab and pertuzumab. TRIAL REGISTRATION: This trial was registered in Japan Registry of Clinical Trials (jCRT) on February 25, 2019, as jRCT2031180150.

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A Japanese patient with ductal carcinoma of the prostate carrying an adenomatosis polyposis coli gene mutation: a case report.

Umeda K, Kosaka T, Nakamura K, Takeda T, Mikami S, Nishihara H, Oya M

Diagnostic pathology 15 （ 1 ） 102 - 102 2020年08月

査読有り

　概要を見る

BACKGROUND: Ductal carcinoma of the prostate is a histological subtype with a higher mortality than acinar adenocarcinoma. The number of cases is small and there are no treatment guidelines. We believe that this is the first report of ductal carcinoma of the prostate with an adenomatosis polyposis coli (APC) gene mutation in Japan. CASE PRESENTATION: An 85-year-old man presented with gross hematuria, and a papillary tumor in the prostatic urethra that was diagnosed as ductal carcinoma of the prostate following transurethral resection. Genetic analysis found an APC mutation with loss of heterozygosity. Immunostaining revealed focal nuclear translocation of β-catenin. APC mutations associated with loss of β-catenin degradation in the Wnt signaling pathway and result in over accumulation of β-catenin are thought to increase mortality. In this patient, β-catenin migrated into tumor cell nuclei. CONCLUSION: To the best of our knowledge, this is the first report of ductal carcinoma of the prostate with an APC mutation in Japan. The development of a therapeutic Wnt inhibitor is discussed.

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[Management of Cancer Genomic Board and Preparation of Genomic Report].

Nakamura K, Nishihara H

Gan to kagaku ryoho. Cancer & chemotherapy 47 （ 8 ） 1141 - 1148 2020年08月

査読有り,  ISSN  0385-0684

Detection of somatic TP53 mutation in surgically resected small-cell lung cancer by targeted exome sequencing: association with longer relapse-free survival.

Yokouchi H, Nishihara H, Harada T, Yamazaki S, Kikuchi H, Oizumi S, Uramoto H, Tanaka F, Harada M, Akie K, Sugaya F, Fujita Y, Takamura K, Kojima T, Higuchi M, Honjo O, Minami Y, Watanabe N, Nishimura M, Suzuki H, Dosaka-Akita H, Isobe H

Heliyon （Elsevier BV）  6 （ 7 ） e04439 - e04439 2020年07月

査読有り,  ISSN  2405-8440

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Next-generation sequencing in residual liquid-based cytology specimens for cancer genome analysis.

Yamaguchi T, Akahane T, Harada O, Kato Y, Aimono E, Takei H, Tasaki T, Noguchi H, Nishihara H, Kamata H, Tanimoto A

Diagnostic cytopathology 48 （ 11 ） 965 - 971 2020年06月

査読有り

　概要を見る

BACKGROUND: Cancer genome profiling of cytology specimens using next-generation sequencing (NGS) requires adequate and good-quality DNA. Genomic examination of cytology samples was conventionally performed on cell block (CB) or smear specimens than on residual liquid-based cytology (LBC) specimens, which are high-quality DNA sources even after long-term storage. METHODS: We estimated tumor fractions of 37 residual LBC specimens, including 30 fine needle aspiration (FNA) samples from the thyroid (12 papillary thyroid carcinomas and two malignant lymphomas), lymph node (13 metastatic carcinomas and one malignant lymphoma), and breast cancer (one phyllodes tumor and one invasive ductal carcinoma), two pancreatic carcinoma samples, and five liquid (ascites, pleural effusion, and cerebrospinal fluid) samples. The DNA was extracted from all samples and subjected to NGS using a customized cancer gene panel comprising 28 cancer-related genes. RESULTS: NGS analysis revealed somatic mutations corresponding to pathological diagnosis with adequate variant allele frequency (VAF) in 24 LBC specimens, which had significantly higher tumor fraction (72.5% ± 4.9%). Ten cases, including the five fluid samples, had very small tumor fractions (7.5% ± 2.3%) to obtain sufficient VAF. Other two samples had high tumor fractions but showed very low VAF, indicating the presence of fusion genes. The remaining one sample yielded no DNA recovery. CONCLUSION: The residual LBC specimens collected by FNA from the thyroid gland and lymph node were verified to carry high tumor fraction and could serve as an alternate source for molecular testing to screen and diagnose cancers without the use of CB or smears.

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Leukotriene B(4) receptor 1 exacerbates inflammation following myocardial infarction.

Horii Y, Nakaya M, Ohara H, Nishihara H, Watari K, Nagasaka A, Nakaya T, Sugiura Y, Okuno T, Koga T, Tanaka A, Yokomizo T, Kurose H

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 34 （ 6 ） 8749 - 8763 2020年06月

査読有り,  ISSN  0892-6638

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Genetic profiling of patients with adenoid cystic carcinoma of the Bartholin's glands reveals potential new routes for targeted therapies: a case report.

Nakamura K, Aimono E, Tanishima S, Nomura H, Imai M, Hayashi H, Nishihara H

Diagnostic pathology 15 （ 1 ） 64 - 64 2020年05月

査読有り

　概要を見る

BACKGROUND: Bartholin gland carcinomas (BGCs) are rare tumor types, for which no molecular analyses including genomic sequencing have been reported to date. Adenoid cystic carcinomas (ACCs) of the Bartholin's glands are an atypical histological type of BGC, and currently nothing is known regarding their genetic profiles or similarity to ACC carcinogenesis in other organs including the salivary glands, thereby limiting possible therapeutic options using precision medicine. CASE PRESENTATION: We used targeted gene sequencing to analyze the occurrence of 160 cancer-related genes in two patients with BG-ACC. KRAS and KDM6A mutations were detected in tumor samples collected from each patient. No KRAS mutations have been previously reported in salivary gland ACCs, indicating that the carcinogenesis of BG-ACC differs from that of the salivary gland ACCs. KDM6A mutations are often reported in salivary gland ACCs and facilitate novel gene-targeted therapy, including the use of BET and HDAC inhibitors. CONCLUSIONS: A better understanding of the underlying genetic mechanisms will help to clarify the carcinogenesis of BG-ACC. In turn, this will enable treatment with novel targeting agents, as well as the initial exploration of gene-based precision oncological therapies, which aim to improve treatment outcomes for patients with this disease.

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Osimertinib Overcomes Alectinib Resistance Caused by Amphiregulin in a Leptomeningeal Carcinomatosis Model of ALK-Rearranged Lung Cancer.

Arai S, Takeuchi S, Fukuda K, Taniguchi H, Nishiyama A, Tanimoto A, Satouchi M, Yamashita K, Ohtsubo K, Nanjo S, Kumagai T, Katayama R, Nishio M, Zheng MM, Wu YL, Nishihara H, Yamamoto T, Nakada M, Yano S

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 15 （ 5 ） 752 - 765 2020年05月

査読有り,  ISSN  1556-0864

　概要を見る

INTRODUCTION: Leptomeningeal carcinomatosis (LMC) occurs frequently in anaplastic lymphoma kinase (ALK)-rearranged NSCLC and develops acquired resistance to ALK tyrosine kinase inhibitors (ALK TKIs). This study aimed to clarify the resistance mechanism to alectinib, a second-generation ALK TKI, in LMC and test a novel therapeutic strategy. METHODS: We induced alectinib resistance in an LMC mouse model with ALK-rearranged NSCLC cell line, A925LPE3, by continuous oral alectinib treatment, established A925L/AR cells. Resistance mechanisms were analyzed using several assays, including Western blot and receptor tyrosine kinase array. We also measured amphiregulin (AREG) concentrations in cerebrospinal fluid from patients with ALK-rearranged NSCLC with alectinib-refractory LMC by enzyme-linked immunosorbent assay. RESULTS: A925L/AR cells were moderately resistant to various ALK TKIs, such as alectinib, crizotinib, ceritinib, and lorlatinib, compared with parental cells in vitro. A925L/AR cells acquired the resistance by EGFR activation resulting from AREG overexpression caused by decreased expression of microRNA-449a. EGFR TKIs and anti-EGFR antibody resensitized A925L/AR cells to alectinib in vitro. In the LMC model with A925L/AR cells, combined treatment with alectinib and EGFR TKIs, such as erlotinib and osimertinib, successfully controlled progression of LMC. Mass spectrometry imaging showed accumulation of the EGFR TKIs in the tumor lesions. Moreover, notably higher AREG levels were detected in cerebrospinal fluid of patients with alectinib-resistant ALK-rearranged NSCLC with LMC (n = 4), compared with patients with EGFR-mutated NSCLC with EGFR TKI-resistant LMC (n = 30), or patients without LMC (n = 24). CONCLUSIONS: These findings indicate the potential of novel therapies targeting both ALK and EGFR for the treatment of ALK TKI-resistant LMC in ALK-rearranged NSCLC.

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チームアプローチで実現するゲノム医療と薬剤師の役割 がんゲノム医療における患者対応の経験から

四十物 絵理子, 井口 亜橘, 持田 かおり, 今井 光穂, 林 秀幸, 西原 広史

薬学雑誌 （(公社)日本薬学会）  140 （ 5 ） 667 - 668 2020年05月

査読有り,  ISSN  0031-6903

　概要を見る

癌ゲノム医療の現場において、患者の語りを傾聴し、正しく状況を理解すべき職種として、看護師と並んで薬剤師が挙げられる。癌遺伝子外来での患者対応の実情、遺伝性腫瘍症候群について概説し、ゲノム医療における多職種連携の目指すべき姿について述べた。関与する医療者がそれぞれの立場で患者に必要な情報を伝える必要があり、その中でも薬剤師の関与は重要であると考えられた。

Excessive EP4 Signaling in Smooth Muscle Cells Induces Abdominal Aortic Aneurysm by Amplifying Inflammation.

Hiromi T, Yokoyama U, Kurotaki D, Mamun A, Ishiwata R, Ichikawa Y, Nishihara H, Umemura M, Fujita T, Yasuda S, Minami T, Goda M, Uchida K, Suzuki S, Takeuchi I, Masuda M, Breyer RM, Tamura T, Ishikawa Y

Arteriosclerosis, thrombosis, and vascular biology 40 （ 6 ） ATVBAHA120314297 - 1573 2020年04月

査読有り,  ISSN  1079-5642

　概要を見る

OBJECTIVE: Excessive prostaglandin E2 production is a hallmark of abdominal aortic aneurysm (AAA). Enhanced expression of prostaglandin E2 receptor EP4 in vascular smooth muscle cells (VSMCs) has been demonstrated in human AAAs. Although moderate expression of EP4 contributes to vascular homeostasis, the roles of excessive EP4 in vascular pathology remain uncertain. We aimed to investigate whether EP4 overexpression in VSMCs exacerbates AAAs. Approach and Results: We constructed mice with EP4 overexpressed selectively in VSMCs under an SM22α promoter (EP4-Tg). Most EP4-Tg mice died within 2 weeks of Ang II (angiotensin II) infusion due to AAA, while nontransgenic mice given Ang II displayed no overt phenotype. EP4-Tg developed much larger AAAs than nontransgenic mice after periaortic CaCl2 application. In contrast, EP4fl/+;SM22-Cre;ApoE-/- and EP4fl/+;SM22-Cre mice, which are EP4 heterozygous knockout in VSMCs, rarely exhibited AAA after Ang II or CaCl2 treatment, respectively. In Ang II-infused EP4-Tg aorta, Ly6Chi inflammatory monocyte/macrophage infiltration and MMP-9 (matrix metalloprotease-9) activation were enhanced. An unbiased analysis revealed that EP4 stimulation positively regulated the genes binding cytokine receptors in VSMCs, in which IL (interleukin)-6 was the most strongly upregulated. In VSMCs of EP4-Tg and human AAAs, EP4 stimulation caused marked IL-6 production via TAK1 (transforming growth factor-β-activated kinase 1), NF-κB (nuclear factor-kappa B), JNK (c-Jun N-terminal kinase), and p38. Inhibition of IL-6 prevented Ang II-induced AAA formation in EP4-Tg. In addition, EP4 stimulation decreased elastin/collagen cross-linking protein LOX (lysyl oxidase) in both human and mouse VSMCs. CONCLUSIONS: Dysregulated EP4 overexpression in VSMCs promotes inflammatory monocyte/macrophage infiltration and attenuates elastin/collagen fiber formation, leading to AAA exacerbation.

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