i(3)so3-galactosylceramide and Colorectal-Neoplasms

The nature of the regulatory cell types that dominate in any given tumor is not understood at present. Here, we addressed this question for regulatory T cells (Treg) and type II natural killer T (NKT) cells in syngeneic models of colorectal and renal cancer. In mice with both type I and II NKT cells, or in mice with neither type of NKT cell, Treg depletion was sufficient to protect against tumor outgrowth. Surprisingly, in mice lacking only type I NKT cells, Treg blockade was insufficient for protection. Thus, we hypothesized that type II NKT cells may be neutralized by type I NKT cells, leaving Tregs as the primary suppressor, whereas in mice lacking type I NKT cells, unopposed type II NKT cells could suppress tumor immunity even when Tregs were blocked. We confirmed this hypothesis in 3 ways by reconstituting type I NKT cells as well as selectively blocking or activating type II NKT cells with antibody or the agonist sulfatide, respectively. In this manner, we showed that blockade of both type II NKT cells and Tregs is necessary to abrogate suppression of tumor immunity, but a third cell, the type I NKT cell, determines the balance between these regulatory mechanisms. As patients with cancer often have deficient type I NKT cell function, managing this delicate balance among 3 T-cell subsets may be critical for the success of immunotherapy for human cancer.

Topics: Animals; Cell Line, Tumor; Colorectal Neoplasms; Female; Kidney Neoplasms; Mice; Mice, Inbred BALB C; Natural Killer T-Cells; Sulfoglycosphingolipids; T-Lymphocyte Subsets; T-Lymphocytes, Regulatory

Sulfatide is a glycosphingolipid known to interact with several extracellular matrix proteins, such as tenascin-C which is overexpressed in many types of cancer including that of the colon. In view of the limited success of chemotherapy in colorectal cancer and high toxicity of doxorubicin (DOX), a sulfatide-containing liposome (SCL) encapsulation approach was taken to overcome these barriers. This study assessed the in vitro cytotoxicity, biodistribution, therapeutic efficacy and systemic toxicity in vivo of sulfatide-containing liposomal doxorubicin (SCL-DOX) using human colonic adenocarcinoma HT-29 xenograft as the experimental model. In vitro, SCL-DOX was shown to be delivered into the nuclei and displayed prolonged retention compared with the free DOX. The use of this nanodrug delivery system to deliver DOX for treatment of tumor-bearing mice produced a much improved therapeutic efficacy in terms of tumor growth suppression and extended survival in contrast to the free drug. Furthermore, treatment of tumor-bearing mice with SCL-DOX resulted in a lower DOX uptake in the principal sites of toxicity of the free drug, namely the heart and skin, as well as reduced myelosuppression and diminished cardiotoxicity. Such natural lipid-guided nanodrug delivery systems may represent a new strategy for the development of effective anticancer chemotherapeutics targeting the tumor microenvironment for both primary tumor and micrometastases.

Topics: Animals; Antineoplastic Agents; Colorectal Neoplasms; Doxorubicin; Drug Delivery Systems; Female; HT29 Cells; Humans; Liposomes; Mice; Mice, Inbred BALB C; Sulfoglycosphingolipids; Tumor Microenvironment; Xenograft Model Antitumor Assays

Sulfatide is one of the acidic glycolipids that are components of the cellular membrane. It has been reported that sulfatide plays some important roles in cell functions, such as cell adhesion. The aim of this study was to investigate the relationship between sulfatide and the malignant potential of colorectal carcinoma.. Glycolipids were extracted from 22 primary colorectal cancer tumors and 6 adjacent normal mucosa using the Folch method. Qualitative analysis of the sulfatide contents was performed using thin-layer chromatography (TLC) and TLC immunostaining. Quantitative analysis was performed by densitometric scanning.. Two bands of sulfatide were observed by TLC immunostaining and were designated as cerebroside sulfated ester (CSE)-A and CSE-B. Levels of CSE-A were found to be significantly decreased whereas those of CSE-B were significantly increased in cancerous tissue when compared with normal tissue (P<0.05). The CSE ratios (CSE-B/[CSE-A + CSE-B]) in the 15 tumors showing lymph node metastasisi were higher than in the 7 tumors without lymph node metastasis (P<0.05). The CSE ratios in 9 Dukes Stage C tumors and 6 Dukes Stage D tumors were higher than those in 7 Dukes Stage A tumors (P<0.02, and P<0.05, respectively).. These data support the conclusion that changes in sulfatide composition may play an important role in lymph node metastasis of colorectal adenocarcinoma.

Topics: Aged; Aged, 80 and over; Biomarkers, Tumor; Chromatography, Thin Layer; Colon; Colorectal Neoplasms; Female; Humans; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Rectum; Sulfoglycosphingolipids