マウスモデルにおいて腫瘍部へのCCR1陽性骨髄球の集簇を阻害すると腫瘍の増殖・転移が抑制される

京都大学0048新制・課程博士博士(医学)甲第22740号医博第4658号新制||医||1046(附属図書館)京都大学大学院医学研究科医学専攻(主査)教授 羽賀 博典, 教授 髙折 晃史, 教授 伊藤 貴浩学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDFA

Laparoscopic ventral rectopexy with sacrocolpopexy for coexisting pelvic organ prolapse and external rectal prolapse

Objectives: Pelvic organ prolapse (POP) POP is defined as the protrusion of pelvic organs from the vaginal canal. POP often coexists with internal rectal prolapse or external rectal prolapse (ERP). A series of patients with coexisting POP and ERP who underwent laparoscopic ventral rectopexy (LVR) combined with laparoscopic sacrocolpopexy (LSC) are reported here. Methods: Seven patients underwent LVR and LSC together. Fecal incontinence was assessed by the Fecal Incontinence Severity Index (FISI), constipation was assessed by the Constipation Scoring System (CSS), and urinary incontinence was assessed by the International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF). Anatomical disorders were assessed by Pelvic Organ Prolapse Quantification (POP-Q) and defecography. Results: The patients' median age was 81 (60-88) years. The median operative time was 380 (282-430) minutes. The median postoperative hospital stay was 3 (1-5) days. There were no postoperative complications. The FISI, CSS, POP-Q, and defecography findings improved postoperatively; however, the ICIQ-SF deteriorated in 2 of 5 patients. Conclusions: LVR combined with LSC for coexisting POP and ERP is feasible

The Role of Tumor-Associated Neutrophils in Colorectal Cancer

Colorectal cancer (CRC) is one of the most common causes of cancer deaths worldwide and the number of CRC patients is increasing progressively. Despite the improvement of the surgical techniques and chemotherapy, we have not completely overcome this disease yet due to the metastases. Therefore, understanding the mechanisms through which metastasis occurs is important for overcoming CRC. Normal host cells in the tumor microenvironment, such as macrophages and fibroblasts, have been reported to promote the growth of CRCs. Although neutrophils were originally considered to have defensive functions against tumor cells, it has been revealed that some populations of neutrophils, called as tumor-associated neutrophils (TANs), have tumor-supportive functions. The plasticity between tumor-suppressive and -supportive neutrophils are regulated by transforming growth factor (TGF)-β and Interferon-β signaling. Some studies have demonstrated that TANs promote the spread of cancer cells to distant organs. TANs contribute to the tumor invasion and angiogenesis through the production of matrix metalloproteinase-9 (MMP9), vascular endothelial growth factor (VEGF), and hepatocyte growth factor (HGF) in the primary and metastatic sites. Neutrophils also promotes tumor cell dissemination by capturing circulating tumor cells using neutrophil extracellular traps and promote their migration to distant sites. The neutrophil-to-lymphocyte ratio is a well-defined predictive marker for CRC patients. In this review, we highlight the molecular signaling between TANs and CRC cells and the possibility of TANs as a potential target for cancer therapy

Disruption of CCR1-mediated myeloid cell accumulation suppresses colorectal cancer progression in mice

Tumor-stromal interaction is implicated in tumor progression. Although CCR1 expression in myeloid cells could be associated with pro-tumor activity, it remains elusive whether disruption of CCR1-mediated myeloid cell accumulation can suppress tumor progression. Here, we investigated the role of CCR1 depletion in myeloid cells in two syngeneic colorectal cancer mouse models: MC38, a transplanted tumor model and CMT93, a liver metastasis model. Both cells induced tumor accumulation of CCR1+ myeloid cells that express MMP2, MMP9, iNOS, and VEGF. Lack of the Ccr1 gene in host mice dramatically reduced MC38 tumor growth as well as CMT93 liver metastasis. To delineate the contribution of CCR1+ myeloid cells, we performed bone marrow (BM) transfer experiments in which sub-lethally irradiated wild-type mice were reconstituted with BM from either wild-type or Ccr1-/- mice. Mice reconstituted with Ccr1-/- BM exhibited marked suppression of MC38 tumor growth and CMT93 liver metastasis, compared with control mice. Consistent with these results, administration of a neutralizing anti-CCR1 monoclonal antibody, KM5908, significantly suppressed MC38 tumor growth and CMT93 liver metastases. Our findings highlight the importance of the application of CCR1 blockade as a therapeutic strategy

Neutrophil Extracellular Traps Promote Metastases of Colorectal Cancers through Activation of ERK Signaling by Releasing Neutrophil Elastase

Neutrophil extracellular traps (NETs) play important roles in host immunity, as there is increasing evidence of their contribution to the progression of several types of cancers even though their role in colorectal cancers (CRCs) remains unclear. To investigate the clinical relevance of NETs in CRCs, we examined the expression of citrullinated histone H3 using immunohistochemistry and preoperative serum myeloperoxidase–DNA complexes in CRC patients using an enzyme-linked immunosorbent assay. High expression of intratumoral or systemic NETs was found to correlate with poor relapse-free survival (RFS), for which it is an independent prognostic factor. In vitro investigations of CRC cells (HCT116, HT29) revealed that NETs did not affect their proliferation but did promote the migration of CRC cells mediated by neutrophil elastase (NE) released during NETosis to increase extracellular signal-regulated kinase (ERK) activity. In vivo experiments using nude mice (KSN/slc) revealed that NE inhibition suppressed liver metastases in CRC cells, although it did not affect the growth of subcutaneously implanted tumors. Taken together, these results suggest that NET formation correlates with poor prognoses of patients with CRC and that the inhibition of NE could be a potential therapy for CRC metastases