Prostaglandin E2/EP signaling in the tumor microenvironment of colorectal cancer

This article belongs to the Special Issue Molecular and Translational Research on Colorectal CancerThe 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

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

The P.H. and Proteins in the Saliva of Patients with Cervical Carcinoma

As the auxiliary diagnosis for carcinoma of the cervix the author evaluated the pH, whole proteins. and protein fractions in the saliva; and obtained the following results: 1) The pH of the saliva in patients with cervical carcinoma is lower than that in the case of normal non-pregnant women, and it becomes more marked with the lapse of time. In 25.6 per cent of the patients in Stage Ⅰ an abnormally low pH of under 6.2 can be observed, showing a significant difference as compared with the normal non-pregnant women; but as the percentage is low, it can not be so useful for an early diagnosis. 2) In 9.6 per cent of those whose improvement is good at follow-up examinations after treatment such an abnormally low pH can be found, and in them pH returns to the normal level only after one year. In 33.3 per cent of those whose prognosis is poor, an abnormally low pH value can be recognized. In the follow-up examinations successively abnormally low pH can be found in 8.0 per cent of those with a good improvement, and in 66.6 per cent of those with a poor improvement. Sixty per cent of those showing abnormally low pH successively are those with a poor prognosis. 3) The amount of whole protein in the saliva of patient with cervical carcinoma shows a slight increase over 46.2 mg/dl in the case of normal non-pregnant women. Statistically a significant difference at 79.0 mg/dl can only be recognized in those at Stage Ⅳ. As for the percentage of those showing as abnormally high as 72.26 mg/dl, 28.9 per cent of those in Stage Ⅱ show abnormally high value as compared with normal non-pregnant women, but it has little value for diagnosis. 4) An increase in whole protein can be recognized in the anemic patient showing sahli value of under 59 per cent. 5) No significant difference can be recognized in the protein fractions of the saliva in the patients with cervical carcinoma as compared with normal non-pregnant women. From these data it is assumed that the evaluations of the whole protein content and protein fractions in the saliva are not so useful as an auxiliary diagnosis of cervical carcinoma, but the continuous follow-up estimations of pH of the saliva for the purpose of discovering the recurrence of cervical carcinoma at an early stage enable us to foresee it, and such follow-up examinations will offer us an important criterion for the judging of the conditions after treatment

Fluorescence diagnosis of metastatic lymph nodes using 5-aminolevulinic acid (5-ALA) in a mouse model of colon cancer.

[Background]Lymph node metastasis is one of the most critical prognostic factors in patients with colorectal cancer. Although regional lymph nodes should be surgically resected and pathologically examined, techniques for the intraoperative diagnosis of lymph node metastasis remain to be well established. Fluorescence diagnosis using 5-aminolevulinic acid (5-ALA) is a promising technique for evaluating various malignancies. After exogenous administration of 5-ALA, protoporphyrin IX (PPIX) accumulates in malignant cells and can be detected as red fluorescence. In this study, we investigated the usefulness of fluorescence diagnosis using 5-ALA for the detection of lymph node metastasis in a mouse model of colon cancer. [Materials and Methods]An orthotopic colon cancer model was prepared by inoculating the cecal wall of nude mice with HCA7, a human colon adenocarcinoma cell line. After 3 wk, 40 mg/kg of 5-ALA was administered intraperitoneally (IP) or orally (PO). Fluorescence diagnosis with a D-Light System (Karl Storz) was then performed after 3 or 6 h. [Results]In the IP group, PPIX fluorescence was detected in metastatic lymph nodes as well as in other malignant lesions, including primary tumors and abdominal implantations, while non-metastatic nodes were fluorescence-negative. In contrast, no obvious fluorescence was detected in cancerous tissues in the PO group. [Conclusions]PPIX fluorescence induced by intraperitoneal injection of 5-ALA allows metastatic lymph nodes to be accurately diagnosed in this mouse model. This technique may facilitate the intraoperative diagnosis of lymph node metastases from colon cancer in a clinical setting

Chitinase 3-Like 1 Promotes Macrophage Recruitment and Angiogenesis in Colorectal Cancer

Chitinase 3-like 1 (CHI3L1), one of mammalian members of the chitinase family, is expressed in several types of human cancer, and elevated serum level of CHI3L1 is suggested to be a biomarker of poor prognosis in advanced cancer patients. However, the overall biological function of CHI3L1 in human cancers still remains unknown. Studies were performed to characterize the role of CHI3L1 in cancer pathophysiology utilizing human colorectal cancer samples and human cell lines. Plasma protein and tissue mRNA expression levels of CHI3L1 in colorectal cancer were strongly upregulated. Immunohistochemical analysis showed that CHI3L1 was expressed in cancer cells and CHI3L1 expression had a significant association with the number of infiltrated macrophages and microvessel density. By utilizing trans-well migration and tube formation assays, overexpression of CHI3L1 in SW480 cells (human colon cancer cells) enhanced the migration of THP-1 cells (human macrophage cells) and HUVECs (human endothelial cells), and the tube formation of HUVECs. The knockdown of CHI3L1 by RNA interference or the neutralization of CHI3L1 by anti-CHI3L1 antibody displayed strong suppression of CHI3L1-induced migration and tube formation. Cell proliferation assay showed that CHI3L1 overexpression significantly enhanced the proliferation of SW480 cells. ELISA analysis showed that CHI3L1 increased the secretion of inflammatory chemokines, IL-8 and MCP-1, from SW480 cells through mitogen-activated protein kinase (MAPK) signaling pathway. Both neutralization of IL-8 or MCP-1 and inhibition or knockdown of MAPK in SW480 cells significantly inhibited CHI3L1-induced migration and tube formation. In a xenograft mouse model, overexpression of CHI3L1 in HCT116 cells (human colon cancer cells) enhanced the tumor growth as well as macrophage infiltration and microvessel density. In conclusion, CHI3L1 expressed in colon cancer cells promotes cancer cell proliferation, macrophage recruitment and angiogenesis. Thus, the inhibition of CHI3L1 activity may be a novel therapeutic strategy for human colorectal cancer