Transforming growth factor-β signaling pathway in colorectal cancer and its tumor microenvironment

Transforming growth factor-beta (TGF-β) signaling is one of the important cellular pathways that play key roles for tissue maintenance. In particular, it is important in the context of inflammation and tumorigenesis by modulating cell growth, differentiation, apoptosis, and homeostasis. TGF-β receptor type 2 (TGFBR2) mutations affected by a mismatch repair deficiency causes colorectal cancers (CRCs) with microsatellite instability, which is, however, associated with relatively better survival rates. On the other hand, loss of SMAD4, a transcription factor in the TGF-β superfamily signaling, promotes tumor progression. Loss of heterozygosity on chromosome 18 can case SMAD4-deficient CRC, which results in poorer patients’ survival. Such bidirectional phenomenon driven by TGF-β signaling insufficiency reflects the complexity of this signaling pathway in CRC. Moreover, recent understanding of CRC at the molecular level (consensus molecular subtype classification) provides deep insight into the important roles of TGF-β signaling in the tumor microenvironment. Here we focus on the TGF-β signaling in CRC and its interaction with the tumor microenvironment. We summarize the molecular mechanisms of CRC tumorigenesis and progression caused by disruption of TGF-β signaling by cancer epithelial cells and host stromal cells

Strangulated small bowel obstruction caused by isolated obturator nerve and pelvic vessels after pelvic lymphadenectomy in gynecologic surgery: two case reports

[Background] Although small bowel obstruction (SBO) is a major complication occurring after abdominal surgery, few reports have described strangulated SBO after pelvic lymphadenectomy (PL). This report describes two cases of strangulated SBO caused by a skeletonized obturator nerve and pelvic vessels after laparoscopic PL during gynecologic surgery. [Case presentation] Case 1: A 57-year-old woman with endometrial cancer underwent a laparoscopic semi-radical total hysterectomy with PL. Nine months after the operation, she visited our emergency room complaining about subacute pain spreading in the right groin, right buttock, and dorsal part of the right thigh. She had no abdominal pain. Although her symptoms were not typical, computed tomography (CT) revealed strangulated SBO in the right pelvis. Laparoscopic surgery revealed that the small bowel was ischemic. Then we converted to open surgery. We transected the right obturator nerve and umbilical artery, which constructed an internal hernia orifice in the right pelvis, followed by resection of the ischemic small bowel. Fortunately, during 6-month follow-up, she showed only slight difficulty in walking as a postoperative complication. Case 2: A 62-year-old woman with cervical cancer underwent laparoscopic radical hysterectomy with PL. Six months after the operation, she visited our hospital emergently because of sudden onset of abdominal pain and vomiting. CT showed strangulated SBO. Urgent laparoscopic surgery exhibited the incarcerated small bowel at the right pelvis. Consequently, we converted to open surgery. The terminal ileum was detained into the space constructed by the right umbilical artery. We cut the umbilical artery and performed ileocecal resection. After the surgery, she was discharged with no complication or sequela. [Conclusion] When examining a patient after PL who complains of severe pain or symptoms, one should consider the possibility of PL-related SBO, even if the pain is apparently atypical for SBO

Differential involvement of LUBAC‐mediated linear ubiquitination in intestinal epithelial cells and macrophages during intestinal inflammation

Disruption of the intestinal epithelial barrier and dysregulation of macrophages are major factors contributing to the pathogenesis of inflammatory bowel diseases (IBDs). Activation of NF-κB and cell death are involved in maintaining intestinal homeostasis in a cell type-dependent manner. Although both are regulated by linear ubiquitin chain assembly complex (LUBAC)-mediated linear ubiquitination, the physiological relevance of linear ubiquitination to intestinal inflammation remains unexplored. Here, we used two experimental mouse models of IBD (intraperitoneal LPS and oral dextran sodium sulfate [DSS] administration) to examine the role of linear ubiquitination in intestinal epithelial cells (IECs) and macrophages during intestinal inflammation. We did this by deleting the linear ubiquitination activity of LUBAC specifically from IECs or macrophages. Upon LPS administration, loss of ligase activity in IECs induced mucosal inflammation and augmented IEC death. LPS-mediated death of LUBAC-defective IECs was triggered by TNF. IEC death was rescued by an anti-TNF antibody, and TNF (but not LPS) induced apoptosis of organoids derived from LUBAC-defective IECs. However, augmented TNF-mediated IEC death did not overtly affect the severity of colitis after DSS administration. By contrast, defective LUBAC ligase activity in macrophages ameliorated DSS-induced colitis by attenuating both infiltration of macrophages and expression of inflammatory cytokines. Decreased production of macrophage chemoattractant MCP-1/CCL2, as well as pro-inflammatory IL-6 and TNF, occurred through impaired activation of NF-κB and ERK via loss of ligase activity in macrophages. Taken together, these results indicate that both intraperitoneal LPS and oral DSS administrations are beneficial for evaluating epithelial integrity under inflammatory conditions, as well as macrophage functions in the event of an epithelial barrier breach. The data clarify the cell-specific roles of linear ubiquitination as a critical regulator of TNF-mediated epithelial integrity and macrophage pro-inflammatory responses during intestinal inflammation

Effect of herbal medicine daikenchuto on gastrointestinal symptoms following laparoscopic colectomy in patients with colon cancer: A prospective randomized study

We conducted a prospective randomized study to investigate the effect of daikenchuto (DKT) on abdominal symptoms following laparoscopic colectomy in patients with left-sided colon cancer. Patients who suffered from abdominal pain or distention on postoperative day 1 were randomized to either the DKT group or non-DKT group. The primary endpoints were the evaluation of abdominal pain, abdominal distention, and quality of life. The metabolome and gut microbiome analyses were conducted as secondary endpoints. A total of 17 patients were enrolled: 8 patients in the DKT group and 9 patients in the non-DKT group. There were no significant differences in the primary endpoints and postoperative adverse events between the two groups. The metabolome and gut microbiome analyses showed that the levels of plasma lipid mediators associated with the arachidonic acid cascade were lower in the DKT group than in the non-DKT group, and that the relative abundance of genera Serratia and Bilophila were lower in the DKT group than in the non-DKT group. DKT administration did not improve the abdominal symptoms following laparoscopic colectomy. The effects of DKT on metabolites and gut microbiome have to be further investigated

Microrna-9-5p-CDX2 axis: A useful prognostic biomarker for patients with stage II/III colorectal cancer

A lack of caudal-type homeobox transcription factor 2 (CDX2) protein expression has been proposed as a prognostic biomarker for colorectal cancer (CRC). However, the relationship between CDX2 levels and the survival of patients with stage II/III CRC along with the relationship between microRNAs (miRs) and CDX2 expression are unclear. Tissue samples were collected from patients with stage II/III CRC surgically treated at Kyoto University Hospital. CDX2 expression was semi-quantitatively evaluated by immunohistochemistry (IHC). The prognostic impacts of CDX2 expression on overall survival (OS) and relapse-free survival (RFS) were evaluated by multivariable statistical analysis. The expression of miRs regulating CDX2 expression and their prognostic impacts were analyzed using The Cancer Genome Atlas Program for CRC (TCGA-CRC). Eleven of 174 CRC tissues lacked CDX2 expression. The five-year OS and RFS rates of patients with CDX2-negative CRC were significantly lower than those of CDX2-positive patients. Multivariate analysis of clinicopathological features revealed that CDX2-negative status is an independent marker of poor prognosis in stage II/III CRC. miR-9-5p was shown to regulate CDX2 expression. TCGA-CRC analysis showed that high miR-9-5p expression was significantly associated with poor patient prognosis in stage II/III CRC. In conclusion, CDX2, the post-transcriptional target of microRNA-9-5p, is a useful prognostic biomarker in patients with stage II/III CRC

Amino-terminal enhancer of split gene AES encodes a tumor and metastasis suppressor of prostate cancer

A major cause of cancer death is its metastasis to the vital organs. Few effective therapies are available for metastatic castration-resistant prostate cancer (PCa), and progressive metastatic lesions such as lymph nodes and bones cause mortality. We recently identified AES as a metastasis suppressor for colon cancer. Here, we have studied the roles of AES in PCa progression. We analyzed the relationship between AES expression and PCa stages of progression by immunohistochemistry of human needle biopsy samples. We then performed overexpression and knockdown of AES in human PCa cell lines LNCaP, DU145 and PC3, and determined the effects on proliferation, invasion and metastasis in culture and in a xenograft model. We also compared the PCa phenotypes of Aes/Pten compound knockout mice with those of Pten simple knockout mice. Expression levels of AES were inversely correlated with clinical stages of human PCa. Exogenous expression of AES suppressed the growth of LNCaP cells, whereas the AES knockdown promoted it. We also found that AES suppressed transcriptional activities of androgen receptor and Notch signaling. Notably, AES overexpression in AR-defective DU145 and PC3 cells reduced invasion and metastasis to lymph nodes and bones without affecting proliferation in culture. Consistently, prostate epithelium-specific inactivation of Aes in Ptenflox/flox mice increased expression of Snail and MMP9, and accelerated growth, invasion and lymph node metastasis of the mouse prostate tumor. These results suggest that AES plays an important role in controlling tumor growth and metastasis of PCa by regulating both AR and Notch signaling pathways

大腸癌細胞でのSmad4欠損によりCCL15の発現が誘導され、CCR1+骨髄由来細胞が集積し肝転移が促進される

京都大学0048新制・課程博士博士(医学)甲第18127号医博第3847号新制||医||1001(附属図書館)30985京都大学大学院医学研究科医学専攻(主査)教授 千葉 勉, 教授 松田 道行, 教授 野田 亮学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDGA

Treatment of Elderly Patients with Colorectal Cancer

Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. As society ages, the number of elderly patients with CRC will increase. The percentage of patients with right-sided colon cancer and the incidence of microsatellite instability are higher in elderly than in younger patients with CRC. Moreover, the higher incidence of comorbid diseases in elderly patients indicates the need for less invasive treatment strategies. For example, care should be taken in performing additional surgery after endoscopic submucosal dissection for elderly patients with high-risk T1 CRC. Minimally invasive surgery, such as laparoscopic colectomy, would be preferable for elderly patients with CRC. Chemotherapy for elderly patients requires careful monitoring for adverse events. The aim of this review is to summarize the clinicopathological features of CRC in elderly patients, optical surgical strategies, including endoscopic and laparoscopic resection, and chemotherapeutic strategies, including postoperative adjuvant chemotherapy and systemic chemotherapy for unresectable CRC