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  • American Association for Cancer Research (AACR)  (19)
  • 2015-2019  (19)
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  • American Association for Cancer Research (AACR)  (19)
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  • 2015-2019  (19)
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  • 1
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 24, No. 19 ( 2018-10-01), p. 4820-4833
    Abstract: Purpose: Cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) play a central role in tumor progression. We investigated whether CAFs can regulate tumor-infiltrating lymphocytes (TILs) and their role in tumor immunosuppression. Experimental Design: A total of 140 cases of esophageal cancer were analyzed for CAFs and CD8+ or forkhead box protein 3 (FoxP3+) TILs by IHC. We analyzed cytokines using murine or human fibroblasts and cancer cells. Murine-derived fibroblasts and cancer cells were also inoculated into BALB/c or BALB/c-nu/nu mice and the tumors treated with recombinant IL6 or anti-IL6 antibody. Results: CD8+ TILs and CAFs were negatively correlated in intratumoral tissues (P & lt; 0.001), whereas FoxP3+ TILs were positively correlated (P & lt; 0.001) in esophageal cancers. Cocultured Colon26 cancer cells and fibroblasts resulted in accelerated tumor growth in BALB/c mice, along with decreased CD8+ and increased FoxP3+ TILs, compared with cancer cells alone. In vitro, IL6 was highly secreted in both murine and human cancer cell/fibroblast cocultures. IL6 significantly increased Colon26 tumor growth in immune-competent BALB/c (P & lt; 0.001) with fewer CD8+ TILs than untreated tumors (P & lt; 0.001), whereas no difference in BALB/c-nu/nu mice. In contrast, FoxP3+ TILs increased in IL6-treated tumors (P & lt; 0.001). IL6 antibody blockade of tumors cocultured with fibroblasts resulted not only in regression of tumor growth but also in the accumulation of CD8+ TILs in intratumoral tissues. Conclusions: CAFs regulate immunosuppressive TIL populations in the TME via IL6. IL6 blockade, or targeting CAFs, may improve preexisting tumor immunity and enhance the efficacy of conventional immunotherapies. Clin Cancer Res; 24(19); 4820–33. ©2018 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 2
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 4160-4160
    Abstract: Backgrounds: Cancer associated fibroblasts (CAFs) are thought to play an essential role in cancer invasion, migration, metastasis, and tumor immunosuppression. However, there has been still a little evidence of the correlation of tumor immunosuppression and CAFs in human esophageal carcinoma. The other hand, as like rising of PD-1 antibody targeting therapy to tumor immunosuppression have been shown dramatic cure responses in melanoma and now ongoing to other malignancies. Tumor-infiltrating lymphocytes (TILs) are considered typically to represent a host immune response against carcinoma. In many types of tumors TILs have been shown their strong correlation to patient's clinicopathological features. In this study, we evaluated the prognostic correlation of CAFs and TILs, which are classified respectively in tumor-associated CD8+ cytotoxic T lymphocytes (CTL) and FoxP3+ regulatory T cells (Treg) in surgically resected esophageal carcinoma. Materials and methods: Total 58 cases with esophageal carcinoma in our institution were evaluated for the presence of CAFs and TILs by immunohistochemistry. TILs of CTL and Treg were calculated each in the intratumoral and the peripheral tissues, and the cutoff for subgroups was defined at the median value. CAFs were defined as fibroblasts expressing alpha smooth muscle actin (α-SMA), and evaluated with the α-SMA scoring by using “Area Index”, which is calculated by imageJ. TILs and CAFs were assessed for the associations with pathological invasion depth (pT), lymph node metastases (pN), histological types, and disease-free survival (DFS) or overall survival (OS). Result: In intratumoral tissues, Treg was significantly associated with advanced T stages, and Treg and a CTL/Treg ratio were associated with lymph node metastasis. Higher CTL, higher CTL/Treg ratio and lower Treg were significantly associated with improved DFS and OS in univariate analysis. Furthermore, multivariate analysis demonstrated selected higher CTL as an independent prognostic factor (P = 0.010). On the other hand, in peripheral tissues, CTL, Treg, and CTL/Treg ratio were not correlated with clinicopathological factors or the any prognosis. Additionally the overexpression of CAFs was strongly associated with poor prognosis (P = 0.002) and the “Area Index” of α-SMA was inversely correlated with the CTL and CTL/Treg ratio in intratumoral tissues (P = 0.029, 0.017). It suggests that CAFs accumulation in tumor tissue is correlated to status of intratumoral immunesuppression. Conclusion: The CTL in intratumoral tissues are independent prognostic factors, and are considered to play an essential role in tumor immunity. Our results demonstrate that CAFs are significant correlation of immunosuppression in esophageal carcinoma. In the future, targeting CAFs therapy itself might improve tumor immunosuppression, and there is possibility to prolong a prognosis. Citation Format: Takuya Kato, Kazuhiro Noma, Yuki Katsura, Hajime Kashima, Takayuki Ninomiya, Toshiaki Ohara, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara. Prognostic correlation of tumor-infiltrating lymphocytes (TILs) and cancer associated fibroblasts (CAFs) in patients with human esophageal carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4160.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 3
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 1741-1741
    Abstract: Cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) are the most abundant cell population and play a central role in tumor progression. It is currently considered that the TME may strongly affect tumor immunosuppression. We investigated whether CAFs can regulate tumor-infiltrating lymphocytes (TILs) and their role in tumor immunosuppression. 140 cases of esophageal cancer were analyzed for CAFs, and CD8+ or forkhead box protein 3 (FoxP3)+ TILs by immunohistochemistry (IHC). We performed cytokine assays in a co-culture model using murine or human fibroblasts and cancer cells. Murine-derived fibroblasts and cancer cells were also inoculated into BALB/c or BALB/c-nu/nu mice, and the tumors treated with recombinant interleukin 6 (IL-6) or anti-IL-6 antibody. In clinical samples, patients with high CD8+ TIL numbers in intra-tumoral sites had significantly longer OS than those with low numbers (HR = 0.42, 95% CI = 0.25-0.70; P = 0.001). On the other hand, the high FoxP3+ TIL group for intra-tumoral tissues had significantly a shorter OS (HR = 2.82, 95% CI = 1.66-4.78; P & lt; 0.001). However, in peri-tumoral tissues, no significant correlations between CD8+ or FoxP3+ TIL numbers and prognosis were identified. Furthermore, CD8+ TILs and CAFs were negatively correlated in intra-tumoral tissues (P & lt; 0.001), while FoxP3+ TILs and CAFs, were positively correlated (P & lt; 0.001). In vivo, Co-cultured Colon26 cancer cells and NIH/3T3 fibroblasts resulted in subcutaneous tumors with accelerated growth in BALB/c mice, along with decreased CD8+ and increased FoxP3+ TILs, compared with cancer cells alone. Furthermore, the tumor progression ratio of co-cultured group to cancer cells alone group was demonstrated more strongly in BALB/c rather than BALB/c-nu/nu mice, which are immunodeficient mice. In vitro, IL-6 was secreted at high levels in both murine and human cancer cell/fibroblast co-cultures rather than cancer cell/fibroblast alone. Treatment with IL-6 significantly increased growth of Colon26 subcutaneous tumors in immune-competent BALB/c mice (P & lt; 0.001), whereas no difference was observed in BALB/c-nu/nu mice. IHC demonstrated fewer CD8+ TILs in Colon26+IL-6 subcutaneous tumors than in untreated tumors (P & lt; 0.001). In contrast, FoxP3+ TILs increased in IL-6-treated tumors (P & lt; 0.001). IL-6 antibody blockade of tumors co-cultured with fibroblasts resulted not only in regression of tumor growth but also in the accumulation of CD8+ TILs in intra-tumoral tissues. In conclusion, CAFs regulate immunosuppressive TIL populations in the TME via IL-6. IL-6 blockade, or targeting CAFs, may improve pre-existing tumor immunity and enhance the efficacy of conventional immunotherapies. Citation Format: Takuya Kato, Kazuhiro Noma, Yuki Katsura, Hiroaki Sato, Satoshi Kohmoto, Toshiaki Ohara, Hiroshi Tazawa, Yasuhiro Shirakawa, Masaru Inagaki, Toshiyoshi Fujiwara. Cancer-associated fibroblasts regulate intratumoral CD8+/FoxP3+ T cells via interleukin 6 in the tumor immune microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1741.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 4
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 968-968
    Abstract: Background & Aims: MicroRNAs (miRNAs) play a crucial role in diverse cellular biological processes such as differentiation, proliferation, migration, invasion and survival. MiRNA expression patterns are found to be frequently dysregulated in human tumors, which is currently being exploited both from a basic science perspective and for its clinical usefulness as disease biomarkers. Circulating miRNAs are attracting major interest as potential noninvasive biomarkers for colorectal cancer (CRC). This study aimed to identify a novel serum miRNA biomarker for the early detection and/or evaluating prognosis of CRC patients. Methods: Comprehensive miRNA array analysis was performed using serum samples from patients with colorectal neoplasia (CRC: n = 3, adenoma: n = 3) and healthy controls (n = 3). Next, to verify whether the candidate miRNA possessed a secretory potential, we screened miRNA expression levels in culture medium from 2 CRC cell lines, followed by serum analysis from 12 stage IV CRC, 12 adenoma and 12 control subjects. Thereafter, we validated expression of candidate miRNAs in 179 primary CRC tissues, as well as serum samples from an independent cohort of 211 CRCs, 56 adenomas, and 57 control subjects. Results: Through microarray analysis, we identified significantly higher levels of miRNA-1290 (miR-1290) in serum from patients with colorectal adenomas and cancers. We verified miR-1290 overexpression in serum of CRC patients in a training cohort. In the validation cohort, serum miR-1290 levels were significantly upregulated in patients with colorectal adenomas (P & lt; 0.0001) and cancers (P & lt; 0.0001). Serum miR-1290 levels could robustly distinguish adenoma (area under the curve [AUC] = 0.718) and CRC patients (AUC = 0.830) from normal subjects. Serum miR-1290 levels significantly diminished after surgical resection of the primary tumor in the same patients’ serum specimens (P & lt; 0.0001). In addition, we observed a statistically significant positive correlation of miR-1290 expression levels between primary CRC tissues and matched serum samples (ρ = 0.482; P & lt; 0.0001). High miR-1290 expression in serum and tissue was significantly associated with tumor aggressiveness and poor prognosis. Moreover, serum miR-1290 levels were an independent prognostic factor in CRC patients (hazard ratio = 4.51; 95% confidence interval = 1.23-23.69; P = 0.0096). Conclusions: Serum miR-1290, which might be secreted from primary CRC, is a novel diagnostic and prognostic biomarker in CRC. Citation Format: Yuji Toiyama, Hiroki Imaoka, Hiroyuki Fujikawa, Junichiro Hiro, Susumu Saigusa, Koji Tanaka, Yasuhiro Inoue, Yasuhiko Mohri, Takao Mori, Toshio Kato, Ajay Goel, Masato Kusunoki. Circulating microRNA-1290 as a novel diagnostic and prognostic biomarker in human colorectal cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 968.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 5
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. CT123-CT123
    Abstract: Background: Telomerase activation is considered to be a critical step in carcinogenesis and its activity is closely correlated with human telomerase reverse transcriptase (hTERT) expression. We constructed an adenovirus 5 vector OBP-301 (Telomelysin), in which the hTERT promoter drives expression of E1A and E1B genes. OBP-301 causes selective replication and lysis of a variety of human cancer cells, and also inhibits the repair of radiation-induced DNA double-strand breaks, leading to radiosensitization. A phase I study has confirmed the safety and biological activity of intratumoral administration of OBP-301 alone in patients with advanced solid tumors in the United States. To further determine the feasibility, efficacy, and pharmacokinetics of OBP-301 in combination with radiotherapy, a phase I/II study was designed in elderly patients with esophageal cancer. Methods: Patients with histologically confirmed esophageal cancer who were not eligible for standard treatments such as surgery and chemotherapy were enrolled into this study (UMIN000010158). Study treatment consisted of intratumoral needle injections of OBP-301 on days 1, 18, and 32 of treatment. Radiation therapy was administered concurrently over 6 weeks, beginning on day 4, to a total of 60 Gy. Virus administration was performed by intratumoral injection of the primary or metastatic tumor through a flexible endoscope. OBP-301 doses will be escalated initially in cohorts of two for the first 9 patients (1 × 10e10 and 1 × 10e11 virus particles [vp]). Six subsequent patients will receive the highest dose (1 × 10e12 vp). Virus shedding will be monitored in the saliva, sputum, urine, and plasma by a quantitative DNA-PCR assay. Results: Six patients were enrolled and treated in the cohort with 1 × 10e10 vp of OBP-301. The patients comprised 4 males and 2 females, with median age of 83.5 years (range, 68 to 92 years). Only two patients had prior platinum-based chemotherapy. By November 2014, 3 patients completed treatment. All patients developed a transient, self-limited lymphopenia. A 92-year-old female showed a grade 4 lymphopenia classified as being possibly related to the treatment, although it recovered by the interruption of radiation. No other virus-related toxicities were noted. Objective responses were complete response (CR) in 2 patients and partial response (PR) with tumor regression, resulting in reopening of the esophagus, in 1 patient. Pathological analysis in biopsy specimens obtained from completely responded patients demonstrated no viable malignant cells for 3 to 5 months after the treatment completion. Conclusions: Multiple courses of endoscopic OBP-301 injection in combination with locoregional radiotherapy were feasible and well tolerated in elderly patients with esophageal cancer, and appeared to provide clinical benefit. Citation Format: Shunsuke Tanabe, Hiroshi Tazawa, Shunsuke Kagawa, Kazuhiro Noma, Kiyoto Takehara, Takeshi Koujima, Hajime Kashima, Takuya Kato, Shinji Kuroda, Satoru Kikuchi, Yasuhiro Shirakawa, Toshiyoshi Fujiwara. Phase I/II trial of endoscopic intratumoral administration of OBP-301, a novel telomerase-specific oncolytic virus, with radiation in elderly esophageal cancer patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT123. doi:10.1158/1538-7445.AM2015-CT123
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 6
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 15, No. 1 ( 2016-01-01), p. 94-105
    Abstract: S-phase progression of the cell cycle is accelerated in tumors through various genetic abnormalities, and, thus, pharmacologic inhibition of altered cell-cycle progression would be an effective strategy to control tumors. In the current study, we analyzed the antileukemic activity of three available small molecules targeting CDK4/CDK6 against lymphoid crisis of chronic myeloid leukemia (CML-LC) and Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL), and found that all three molecules showed specific activities against leukemic cell lines derived from CML-LC and Ph+ ALL. In particular, PD0332991 exhibited extremely high antileukemic activity against CML-LC and Ph+ ALL cell lines in the nanomolar range by the induction of G0–G1 arrest and partially cell death through dephosphorylation of pRb and downregulation of the genes that are involved in S-phase transition. As an underlying mechanism for favorable sensitivity to the small molecules targeting CDK4/CDK6, cell-cycle progression of Ph+ lymphoid leukemia cells was regulated by transcriptional and posttranscriptional modulation of CDK4 as well as Cyclin D2 gene expression under the control of BCR-ABL probably through the PI3K pathway. Consistently, the gene expression level of Cyclin D2 in Ph+ lymphoid leukemia cells was significantly higher than that in Ph− lymphoid leukemia cells. Of note, three Ph+ ALL cell lines having the T315I mutation also showed sensitivity to PD0332991. In a xenograft model, PD0332991, but not imatinib, suppressed dissemination of Ph+ ALL having the T315I mutation and prolonged survival, demonstrating that this reagent would be a new therapeutic modality for relapsed CML-LC and Ph+ ALL patients after treatment with tyrosine kinase inhibitors. Mol Cancer Ther; 15(1); 94–105. ©2015 AACR.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 7
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 5905-5905
    Abstract: Background: Cancer associated fibroblasts (CAFs) are activated fibroblasts and an important player in the tumor microenvironment. Their activity promotes cancer cell proliferation, migration, and invasion, and metastasis. The most prognostic factor in tumor progression is metastasis. Cancer metastasis is a multi-step process that tumor cells detach from primary site, survive in the bloodstream, and seed in target organ. Although previous studies have focused on the interaction between CAFs and cancer cells in primary tumor site, the roles of CAFs in blood circulation remain largely unknown. We investigated the effect of CAFs coexisting with cancer cells in bloodstream on tumor metastasis in vivo mouse model, and also examined the effect of CAFs in subcutaneous tumor. Methods: We used female BALB/c-nu/nu mice and BALB/c mice in the experiments. Cancer cells were mouse mammary carcinoma cell lines 4T1 transfected with luciferase, colon cancer cell lines Colon 26 transfected with luciferase. Fibroblast cell lines were mouse embryonic fibroblast MEF and NIH-3T3. In venous injection mouse model, we injected 1 × 106 cancer cells alone or the same number of cancer and fibroblast co-cultured together. When we injected cancer cells transfected with luciferase, the mice were subjected to in vivo imaging system (IVIS) and measured luminescence intensity of metastatic sites. We have also harvested lung and compared its weight and metastatic nodule under microscopy. Furthermore, in subcutaneous tumor metastatic mouse model, cancer cells alone or mixed with cancer cells and CAFs were subcutaneously inoculated into the mice. Results: In the group of mice injected with cancer cells and fibroblasts, luminescent intensity of each lungs were higher than cancer cell alone. Harvested lung weight and the number of metastatic nodules were also higher in the group with cancer cells and fibroblasts.In subcutaneous model, mice inoculated with cancer cells and fibroblast had much more metastatic sites than cancer cells alone. Conclusions: Our data indicate that CAFs promote tumor metastasis by stimulating cancer cells in blood circulation, as well as in primary tumor site.These findings suggest that CAFs in both bloodstream and primary site could be a promising therapeutic target. CAF-targeted therapy could reduce tumor metastasis and improve the prognosis of cancer patients. Citation Format: Hajime Kashima, Kazuhiro Noma, Hiroaki Sato, Yuki Katsura, Takuya Kato, Toshiaki Ohara, Hiroshi Tazawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara. Cancer associated fibroblasts promote tumor metastasis coexisting with cancer cells in blood circulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5905. doi:10.1158/1538-7445.AM2017-5905
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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  • 8
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 1952-1952
    Abstract: Background: MicroRNAs (miRNAs) are dysregulated during colorectal cancer (CRC) development and progression. Profiling of CRC tissue has elicited interest in the potential use of miRNAs as non-invasive biomarkers for early detection of CRC. Exosomes have capacity to envelop specific miRNAs, and maintain the integrity of contents in circulation. Therefore, circulating miRNAs in exosomes are more stable than other forms. Thus miRNAs extracted from exosome in serum may have significant potential as disease specific biomarker; however there is no report to assess whether whole serum or exosome-derived miRNAs from serum is a more accurate diagnostic marker and indicator of tumor progression in CRC. This study aimed to evaluate the diagnostic value of serum and exosomal miRNAs for adenoma patients, respectively. Methods: Following a literature review, we investigated the expression of candidate miRNAs in 20 normal colonic mucosa, 27 adenoma, and 19 CRC tissue samples. Then, we quantified their expression in serum and in exosome from 26 adenoma patients and 47 healthy controls to evaluate their clinical significance. Additionally, we compared the expression levels of serum miRNAs with of exosomal miRNAs to investigate their potential as biomarker. Results: We selected four miRNAs, miR-21, miR-29a, miR-92a, and miR-135b, for further investigation. MiR-21, miR-29a, miR-92a, and miR-135b expression in adenoma were significantly higher than in normal colonic mucosa. Regarding the miRNAs expression in serum, miR-21, miR-29a, miR-92a levels in adenoma patients were significantly higher than in healthy controls, and significantly correlated with adenoma size and total adenoma counts in the colorectum. MiR-21, miR-29a and miR-92a levels in serum could significantly discriminate patients with adenoma, and in the patients with advanced adenoma ( & gt;1.0 cm), the capacity to discriminate advanced adenoma improved. On the other hand, exosomal miR-21 and miR-29a levels in serum from adenoma patients were significantly higher than that from healthy volunteer. Only exosomal miR-21 significantly correlated with adenoma size and total adenoma counts in the colorectum, and could differentiate patients with adenomas significantly. In the patients with advanced adenoma, the capacity of exosomal miR-21 for biomarker did not improve, and significance disappeared. Conclusion: Our results revealed that although both serum and exosomal miRNAs could be non-invasive biomarkers for the early detection of CRC, but exosomal miRNAs were unfavorable for the identification of high-risk adenomatous polyps. Serum miR-21, miR-29a and miR-92a are potential diagnostic biomarkers in high-risk adenomatous polyp patients. Citation Format: Ryo Uratani, Yuji Toiyama, Takahito Kitajima, Hiroyuki Fujikawa, Jyunichiro Hiro, Minako Kobayashi, Koji Tanaka, Yasuhiro Inoue, Yasuhiko Mohri, Takao Mori, Toshio Kato, Ajay Goel, Masato Kusunoki. Diagnostic potential of serum and exosomal microRNAs for patients with pre-malignant lesions of colorectal cancer: Detection of adenoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1952.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 9
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. LB-310-LB-310
    Abstract: Esophageal cancer is known to one of the most aggressive malignant tumors, however, the effect of conventional chemotherapy and radiotherapy is insufficiently. Cancer-associated fibroblasts (CAFs) are thought to play an essential role in cancer invasion, migration, metastasis, immunosuppression, and resistance to anticancer drugs. Previously, we have developed a novel near-infrared photoimmunotherapy (NIR-PIT) targeting CAFs, which induces the selective destruction by targeting specific surface protein of CAFs; fibroblast activation protein (FAP). The aim of this study is to analyze the influence of CAFs for human esophageal cancer and to evaluate the improvement of conventional therapeutic resistance using NIR-PIT targeting CAFs.We produced the IR700-FAP antibody for this study. Human esophageal cancer cell lines (TE4 and OE19) and FEF3 human fibroblasts were used. At first, we demonstrated that cancer cells stimulated by CAFs acquired resistance to conventional therapies by cell viability assay. Furthermore, invasion, migration, and colony-formation assays demonstrated the CAF-stimulated cancer cells had a more malignant phenotype. Western blotting analysis showed that E-cadherin expression was decreased and vimentin expression was increased in CAF-stimulated cancer cells, indicating the epithelial mesenchymal transition induction. In vivo experiments demonstrated that subcutaneous tumors co-injected with CAFs were more refractory to chemotherapy than the tumors without CAFs as same as observed in vitro. Secondary, we found that acquired therapeutic resistance in stimulated cancer cells were restored by excluding continuous stimulation of CAFs. Finally, we investigated whether depleting CAFs by NIR-PIT could affect the chemo-resistance of cancer cells in vitro and in vivo. To evaluate the combination effect of conventional chemotherapy and NIR-PIT in vivo, xenograft models co-injected TE4 cells with CAFs were treated with 5-FU plus NIR-PIT, 5-FU alone, or PBS as control. 5-FU alone therapy could not suppress tumor growth, however combination therapy as 5-FU plus NIR-PIT could suppress tumor growth compared to control significantly. These results demonstrated that CAFs gave human esophageal cancer cells higher malignant and resistant phenotype, which could be overcome by using NIR-PIT targeting CAFs. Targeting fibroblast itself is a unique strategy and can be clinically promising as combination targeting cancer cells and their fundamental microenvironment, CAFs. Citation Format: Satoshi Komoto, Kazuhiro Noma, Ryoichi Katsube, Takuya Kato, Toshiaki Ohara, Hiroaki Sato, Toru Narusaka, Noriyuki Nisiwaki, Hiroshi Tazawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara. Overcoming resistance of conventional therapies by targeting cancer-associated fibroblasts (CAFs) with near-infrared photoimmunotherapy (NIR-PIT) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-310.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 10
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 5934-5934
    Abstract: Background: As like rising of PD-1 antibody, targeting therapy to tumor immunosuppression have been shown dramatic cure responses in melanoma and other malignancies. However there are still problems that the responders of those checkpoint inhibitors are limited. Recently, it is considered that tumor immunosuppression may be caused by not only cancer cells but also tumor microenvironments (TME). Cancer-associated fibroblasts (CAFs) are one of the major components and have a central role for tumor progression in TME. It has been hypothesized that they can also play an essential role in tumor immunosuppression. In this study, we evaluated the correlation between CAFs and tumor immunity system, especially tumor-infiltrating lymphocytes (TILs) in clinical samples and further in vivo study. Materials and methods: Total 140 cases of esophageal cancer were evaluated for the presence of CAFs and TILs by immunohistochemistry (IHC). CAFs were defined as fibroblasts expressing alpha smooth muscle actin. CD8+ cytotoxic T lymphocytes and FoxP3+ regulatory T cells were investigated as TILs in each specimen’s intratumoral and peritumoral tissues. The outcome was set as the correlation between CAFs and TILs, and Overall survival. In vivo experiments, we used a mouse-derived cancer cell (colon26-Luc) and mouse embryonic fibroblasts (NIH/3T3). BALB/c or BALB/c-nu/nu mice were inoculated with only cancer cells (control) or cancer cells with CAFs (co-CAFs) into right flank to examine the immunosuppression affected by CAFs. The proliferation was examined by in vivo imaging system. Result: In clinical analysis, CD8+ TILs and CAFs demonstrated strong relations, which were significantly “negative” correlation and showed moderate correlation coefficient in intratumoral tissues (P & lt;0.001, r=-0.416). In FoxP3+ TILs, “positive” correlation was detected significantly (P & lt;0.001, r=0.484). In terms of prognosis, high group of CD8+ TILs had a good prognosis significantly (P & lt;0.001), whereas high group of FoxP3+ TILs had a poor prognosis significantly (P & lt;0.001) in intratumoral tissues. However, there was no difference of the correlation and the prognosis in peritumoral tissues. In vivo experiments demonstrated that promoted ratio of tumor progression by co-CAFs was more strongly demonstrated in BALB/c mice rather than BALB/c-nu/nu mice, suggesting that the group co-CAFs showed inducing immunosuppression in TME. IHC analysis of those tumors showed that accumulation of CD8+ TILs was decreased in tumors of co-CAFs as compared with tumors of control. On the other hand, accumulation of FoxP3+ TIL was increased, showing the same trends as clinical analysis. Conclusion: Our results suggest that Both CD8+ and FoxP3+ TILs in intratumoral tissues are independent prognostic factors, and CAFs have a significant correlation to those TILs. We consider that CAFs may affect tumor immunosuppression by regulating the migration of TILs. Citation Format: Takuya Kato, Kazuhiro Noma, Hajime Kashima, Yuki Katsura, Hiroaki Sato, Takayuki Ninomiya, Toshiaki Ohara, Yasuhiro Shirakawa, Toshiyoshi Fujiwara. Cancer-associated fibroblasts contribute to tumor immunosuppression by regulating tumor-infiltrating lymphocytes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5934. doi:10.1158/1538-7445.AM2017-5934
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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