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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.

Although numerous studies have highlighted the prognostic values of various inflammation-related markers, clinical significance remains to be elucidated. The prognostic values of inflammation-related biomarkers for rectal cancer were investigated in this study. A total of 448 patients with stage II/III rectal cancer undergoing curative resection were enrolled from the discovery cohort (n = 240) and validation cohort (n = 208). We comprehensively compared the prognostic values of 11 inflammation-related markers-derived from neutrophil, lymphocyte, platelet, monocyte, albumin, and C-reactive protein for overall survival (OS) and recurrence-free survival (RFS). Among 11 inflammation-related markers, only “lymphocyte × albumin (LA)” was significantly associated with both OS and RFS in the discovery cohort (P = 0.007 and 0.015, respectively). Multivariate analysis indicated that low LA was significantly associated with poor OS (hazard ratio [HR] 2.19, 95% confidence interval [CI] 1.09–4.58, P = 0.025), and poor RFS (HR 1.61, 95% CI 1.01–2.80, P = 0.048). Furthermore, using the discovery cohort, we confirmed that low LA was significantly associated with poor OS (HR 2.89, 95% CI 1.42–6.00, P = 0.002), and poor RFS (HR 1.79, 95% CI 1.04–2.95, P = 0.034). LA can be a novel prognostic biomarker for stage II/III rectal cancer.

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.

Background Technical difficulties in rectal surgery are often related to dissection in a limited surgical field. This study investigated the clinical value of MRI pelvimetry in the prediction of surgical difficulty associated with minimally invasive rectal surgery. Methods Patients with rectal cancer who underwent laparoscopic or robotic total mesorectal excision between 2005 and 2017 were reviewed retrospectively and categorized according to surgical difficulty on the basis of duration of surgery, conversion to an open procedure, use of the transanal approach, postoperative hospital stay, blood loss and postoperative complications. Preoperative clinical and MRI‐related parameters were examined to develop a prediction model to estimate the extent of surgical difficulty, and to compare anastomotic leakage rates in the low‐ and high‐grade surgical difficulty groups. Prognosis was investigated by calculating overall and relapse‐free survival, and cumulative local and distant recurrence rates. Results Of 121 patients analysed, 104 (86·0 per cent) were categorized into the low‐grade group and 17 (14·0 per cent) into the high‐grade group. Multivariable analysis indicated that high‐grade surgical difficulty was associated with a BMI above 25 kg/m2 (odds ratio (OR) 4·45, P = 0·033), tumour size 45 mm or more (OR 5·42, P = 0·042), anorectal angle 123° or more (OR 5·98, P = 0·028) and pelvic outlet less than 82·7 mm (OR 6·62, P = 0·048). All of these features were used to devise a four‐variable scoring model to predict surgical difficulty. In patients categorized as high grade for surgical difficulty, the anastomotic leakage rate was 53 per cent (9 of 17 patients), compared with 9·6 per cent (10 of 104) in the low‐grade group (P, This study highlights the impact of MRI pelvimetry in predicting surgical difficulty in laparoscopic rectal surgery. Multivariable analysis identified that surgical difficulty was significantly associated with four variables: BMI, tumour size, anorectal angle and pelvic outlet. A novel scoring model using these four variables to predict surgical difficulty is proposed. MRI pelvimetry and TME difficulty

Although the application of laparoscopic rectal surgery has been widely accepted by accumulated evidence, it remains technically difficult in some cases of obesity, narrow male pelvis, bulky tumors, or involvement of adjacent organs. After robotic rectal surgery has been covered by the health insurance system in Japan since April 2018, we have employed robotic rectal surgery for an increasing number of cases by taking advantages of its 3D vision and wrist function. When a colorectal cancer involves the urinary bladder, the surgical treatment of choice is an anterior resection with en bloc (partial or total) bladder resection, depending on the site and extent of bladder involvement. In the attached video, robotic surgery was conducted with the aid of intraoperative cystoscopy, which resulted in curative resection with negative margin. Given that the robotic system provides excellent stability and dexterity for bladder reconstruction, the robotic approach can be technically suitable for locally advanced T4 colorectal cancer with urinary involvement. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13691-020-00413-7) contains supplementary material, which is available to authorized users.

Most colorectal cancers (CRCs) are moderately differentiated or well differentiated, a status that is preserved even in metastatic tumors. However, the molecular mechanisms underlying CRC differentiation remain to be elucidated. Herein, we unravel a potentially novel posttranscriptional regulatory mechanism via a LIN28B/CDX2 signaling axis that plays a critical role in mediating CRC differentiation. Owing to a large number of mRNA targets, the mRNA-binding protein LIN28B has diverse functions in development, metabolism, tissue regeneration, and tumorigenesis. Our RNA-binding protein IP (RIP) assay revealed that LIN28B directly binds CDX2 mRNA, which is a pivotal homeobox transcription factor in normal intestinal epithelial cell identity and differentiation. Furthermore, LIN28B overexpression resulted in enhanced CDX2 expression to promote differentiation in subcutaneous xenograft tumors generated from CRC cells and metastatic tumor colonization through mesenchymal-epithelial transition in CRC liver metastasis mouse models. A ChIP sequence for CDX2 identified α-methylacyl-CoA racemase (AMACR) as a potentially novel transcriptional target of CDX2 in the context of LIN28B overexpression. We also found that AMACR enhanced intestinal alkaline phosphatase activity, which is known as a key component of intestinal differentiation, through the upregulation of butyric acid. Overall, we demonstrated that LIN28B promotes CRC differentiation through the CDX2/AMACR axis.

Background The global pandemic of COVID-19 has changed cancer treatment environments. In Japan, cancer screenings were halted and the numbers of endoscopies and surgeries were restricted in some hospitals based on the state of emergency declared. Herein, we investigated the impact of the COVID-19 pandemic on the characteristics of colorectal cancer (CRC) patients in facilities that are on the frontline of both COVID-19 and cancer treatments. Patients and methods We retrospectively analyzed the cases of all of the CRC patients (n = 123) who underwent surgery at our regional cancer treatment center and tertiary emergency hospital in Japan during a 120-day period ranging from before to after the state of emergency declaration. CRC patients during the corresponding period in the previous year were also examined. Results Although the number of CRC patients did not show a significant change related to the pandemic, the incidence of obstructive CRCs significantly increased after the pandemic's start. The numbers of outpatients and colonoscopies both decreased, which could have resulted in the decrease of CRC patients detected by cancer screening during the pandemic. The numbers of symptomatic CRC patients and emergency admissions both increased significantly during the pandemic. Conclusion Our findings indicate the possibility that the discovery of CRCs in patients could be delayed due to the halt in screenings caused by the COVID-19 pandemic, resulting in the increase of obstructive CRCs. These results highlight the importance of cancer screening and suggest that the screening system for cancers should be reorganized before future pandemics., Highlights • The number of obstructive colorectal cancer (CRC) patients in Japan has increased during the COVID-19 pandemic, whereas the number of total CRC patients did not change in our regional cancer treatment center/tertiary emergency hospital. • During the COVID-19 pandemic in Japan, the number of CRC patients detected by screening dropped to zero, and the number of patients with abdominal symptoms increased significantly. • It is possible that the delays in the detection of CRCs and surgeries due to halted screenings promoted the progression of CRCs. • The screening systems for cancer should be reorganize before a future pandemic of unknown infectious disease.

Although a number of studies have revealed the underlying mechanisms which regulate the development of colorectal cancer (CRC), we have not completely overcome this disease yet. Accumulating evidence has shown that the posttranscriptional regulation by the noncoding RNAs such as microRNAs plays an important role in the development or progression of CRC. Among a number of microRNAs, thelet-7microRNA family that was first discovered inC. elegansand conserved from worms to humans has been linked with the development of many types of cancers including CRC. The expression level oflet-7microRNAs is temporally low during the normal developmental processes, while elevated in the differentiated tissues. Thelet-7microRNAs regulate the cell proliferation, cell cycle, apoptosis, metabolism, and stemness. In CRC, expressions oflet-7microRNAs have been reported to be reduced, and solet-7microRNAs are considered to be a tumor suppressor. In this review, we discuss the mechanisms regulating thelet-7microRNA expression and the downstream targets oflet-7in the context of intestinal tumorigenesis. The application oflet-7mimics is also highlighted as a novel therapeutic agent.

Background Internal hemorrhoids are the most common anal diseases. Aluminum potassium sulfate and tannic acid (ALTA) injection is a new sclerosing therapy for the treatment of internal hemorrhoids. Although ALTA injection has been widely used, there are no previous reports of rectal cancer patients who underwent robot-assisted low anterior resection (Rob-LAR) after ALTA injection to treat internal hemorrhoids. Case presentation A 70-year-old man with rectal cancer was presented to our hospital. He had an ALTA injection 2 months before presentation at a clinic due to hematochezia with internal hemorrhoids. The rectal tumor was located 7 cm above the anal verge, and Rob-LAR with the da Vinci Xi system was performed. The patient had sclerosis on the stump of the anal side, which made it difficult to transect the rectum with linear staplers. This required multiple repeats of compression through the SmartClamp feedback. After anastomosis with the double-stapling technique, we constructed a diverting ileostomy. Conclusion Although ALTA injection is a promising strategy for internal hemorrhoids, rectal cancer should be excluded before the sclerosing therapy.

Mesenchymal stem cells (MSCs) are recruited from BM to the stroma of developing tumors, where they serve as critical components of the tumor microenvironment by secreting growth factors, cytokines, and chemokines. The role of MSCs in colorectal cancer (CRC) progression was controversial. In this study, we found that C-C chemokine receptor type 5 (CCR5) ligands (i.e., C-C motif chemokine ligand 3 (CCL3), CCL4, and CCL5) were highly produced from MSCs using a chemokine array screening with conditioned media from the cultured human MSCs. A relatively strong CCR5 expression could be detected within the cytoplasm of several CRC cell lines. Regarding the effect of MSC, we found that the xenografts in which CCR5-overexpressing HCT116 cells were inoculated into immunocompromised mice were highly promoted in vivo by a mixture with MSCs. Notably, the CCR5 inhibitor, maraviroc, significantly abolished the MSC-induced tumor growth in vivo. In human clinical specimens (n = 89), 20 cases (29%) were high for CCR5, whereas 69 cases (71%) were low. Statistical analyses indicated that CCR5 expression in primary CRC was associated with CRC patients’ prognosis. Especially, stage III/IV patients with CCR5-high CRCs exhibited a significantly poorer prognosis than those with CCR5-low CRCs. Furthermore, we investigated the effects of preoperative serum CCR5 ligands on patients’ prognosis (n = 114), and found that CRC patients with high serum levels of CCL3 and CCL4 exhibited a poorer prognosis compared to those with low levels of CCL3 and CCL4, while there was no association between CCL5 and prognosis. These results suggest that the inhibition of MSC–CRC interaction by a CCR5 inhibitor could provide the possibility of a novel therapeutic strategy for CRC, and that serum levels of CCL3 and CCL4 could be predictive biomarkers for the prognosis of CRC patients.

Purpose: SMAD4 is a key transcriptional factor of TGFβ signaling and acts as a tumor suppressor in colorectal cancer. In the present study, we explored the immunologic effect of SMAD4 on the tumor microenvironment. Experimental Design: Using 99 clinical specimens and human colorectal cancer cell lines, we investigate the relationship between SMAD4 expression and neutrophil accumulation. We immunohistochemically analyzed expression of SMAD4, CXCL1, CXCL8, CXCR2, and other proteins with clinical specimens. Finally, we determined the serum levels of CXCL1 and CXCL8 in 125 patients with colorectal cancer. Results: SMAD4 knockdown from human colorectal cancer cells upregulated the expression of CXCL1 and CXCL8, which recruited neutrophils to colorectal cancer tumor via CXCR2. In turn, when neutrophils were exposed to the supernatant of SMAD4-negative colorectal cancer cells, they produced a large amount of CXCL1 and CXCL8 by themselves in vitro. In human clinical specimens, we found that neutrophil infiltration into the peritumoral stroma was more marked in SMAD4-negative colorectal cancer compared with that in SMAD4-positive colorectal cancer, and that both CXCL1 and CXCL8 were abundantly expressed in the tumor-infiltrating neutrophils. Neutrophils isolated from primary colorectal cancer expressed significantly higher levels of CXCL1 and CXCL8 than did those isolated from peripheral blood. Furthermore, tumor-infiltrating neutrophils expressed MMP2 and MMP9 in addition to ARG1 and IDO. Serum CXCL8 level was significantly higher in colorectal cancer patients, especially those at stage II/III, and statistical analysis indicated a high CXCL8 level was associated with a shorter overall survival and relapse-free survival. Conclusions: Blockade of the CXCL1/8–CXCR2 axis could be a novel therapeutic approach against SMAD4-negative colorectal cancer.

The number of colorectal cancer (CRC) patients is increasing worldwide. Accumulating evidence has shown that the tumor microenvironment (TME), including macrophages, neutrophils, and fibroblasts, plays an important role in the development and progression of CRC. Although targeting the TME could be a promising therapeutic approach, the mechanisms by which inflammatory cells promote CRC tumorigenesis are not well understood. When inflammation occurs in tissues, prostaglandin E2 (PGE2) is generated from arachidonic acid by the enzyme cyclooxygenase-2 (COX-2). PGE2 regulates multiple functions in various immune cells by binding to the downstream receptors EP1, EP2, EP3, and EP4, and plays an important role in the development of CRC. The current therapies targeting PGE2 using non-steroidal anti-inflammatory drugs (NSAIDs) or COX-2 inhibitors have failed due to the global prostanoid suppression resulting in the severe adverse effects despite the fact they could prevent tumorigenesis. Therefore, therapies targeting the specific downstream molecules of PGE2 signaling could be a promising approach. This review highlights the role of each EP receptor in the TME of CRC tumorigenesis and their therapeutic potential., This article belongs to the Special Issue Molecular and Translational Research on Colorectal Cancer

Desmoid tumors are rare, benign fibromatous lesions that result from the abnormal proliferation of myofibroblasts. A 61-year-old man underwent laparoscopy-assisted right hemicolectomy for ascending colon cancer. The final TNM stage was stage IIIB (T3N1M0). Follow-up computed tomography (CT), done 12 months after primary surgery, showed a nodular, enhancing soft-tissue density mass, 12 mm in size, in the mesentery, near the anastomosis. Another CT scan, done 4 months later, revealed that the tumor had enlarged to 27 mm in size. We suspected locoregional recurrence of colon cancer and resected the tumor, together with the distal ileum and colon, including the previous anastomotic site. The tumor was histologically diagnosed as a desmoid tumor. The patient remains well 24 months after his last operation. Differentiating between the desmoid tumor and locoregional recurrent tumor was difficult, and surgical resection was the optimal treatment.

Introduction: RNA binding proteins and miRNAs have emerged as crucial regulators of intestinal homeostasis by controlling the stability and translation of target mRNAs. LIN28B, an mRNA binding protein, plays a critical role in regulating growth and proliferation in the intestinal epithelium. Previous work in our lab revealed that LIN28B promotes growth and tumorigenesis of the intestinal epithelium via suppression of mature let-7 miRNAs.LIN28B suppression of let-7 promotes upregulation of let-7 targets, including IMP1 (Insulin-like growth factor II mRNA-binding protein 1). Indeed, previous studies from our lab have shown that transgenic mice expressing LIN28B from the mouse Vil1 promoter (Vil-Lin28b mice) have an increase in IMP1 protein levels that is increased further with conditional knockout of let-7. Mechanistically, Let-7 isoforms have been known to physically and functionally interact with IMP1; however, the specific role of IMP1 in Lin28b-let 7-mediated tumorigenesis remains unknown. The current study tested the hypothesis that IMP1 maybe required for LIN28B-mediated tumorigenesis and that LIN28B and IMP1 may cooperatively promote a tumor-initiating phenotype. Methods: We evaluated LIN28B and IMP1 expression and localization in colorectal cancer patient samples using tissue microarrays and clinical outcomes. We used intestinal epithelial cell lines with LIN28B overexpression and CRISPR-Cas9 mediated knockout of IMP1 to study the functional consequences on migration, invasion and proliferation. Results: LIN28B expression correlates with expression of IMP1 in colorectal cancer patient samples. Individually, LIN28B and IMP1 expression intensity each was associated with worse prognosis in stage II colon cancer. Knock-down of IMP1 in Lin28B overexpressing cells decreased migration of colorectal cancer cell lines, suggesting a relationship of IMP1 for the tumorigenic effects of LIN28B. Furthermore, our RNA target analyses show that Lin28b and IMP1 both bind to target mRNAs in the WNT and adherens junction pathways. Conclusions: These data implicate a novel role for the Lin28b-let7-IMP1 axis in colorectal cancer and support an emerging paradigm for a critical and cooperative role of RNA-binding proteins in intestinal homeostasis and cancer. We are using the cell lines generated for orthotopic xenograft studies to see the effects of IMP1 loss and Lin28b overexpression on tumor growth and dissemination. Furthermore, we are generating mice with intestinal epithelium specific Lin28b overexpression-IMP1 loss to study the effects in vivo. Citation Format: Priya Chatterji, Kathryn Hamilton, Sarah Andres, Rei Mizuno, Philip Hicks, Arjun Jeganathan, Monte M. Winslow, Antoni Castells, Miriam Cuatrecasas, Blair Madison, Anil Rustgi. Cooperative functional roles of RNA binding proteins LIN28B and IMP1 in the pathogenesis of 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 1136.