Fatty acid synthase inhibitor cerulenin suppresses liver metastasis of colon cancer in mice.

Fatty acid synthase (FAS) is highly expressed in many kinds of human cancers, including colorectal cancer (CRC), and we have investigated the potential use of FAS inhibitors for chemoprevention of liver metastasis of CRC in mice. Expression of FAS was evaluated in murine CRC cell lines Colon 26 and CMT 93. Cerulenin, a natural inhibitor of FAS, induced apoptosis in these cell lines. The ability of cerulenin to prevent development of liver metastatic lesions in Colon 26 was evaluated. The numbers and sizes of liver metastatic CRC tumors were significantly reduced by treating mice with cerulenin. Cerulenin treatment was associated with reduced levels of phosphorylated Akt in Colon 26 cells, suggesting that inhibition of this signal transduction pathway might be involved in the chemopreventive activity of this compound. Based on studies in mouse models, inhibiting FAS would be an effective strategy to prevent and retard growth of liver metastatic tumors of CRC that have high expression of this enzyme.

Extension of a malignant tailgut cyst to a subcutaneous space in the buttock.

Tailgut cysts are rare benign cystic lesions of the retrorectal space. The recommended treatment is complete resection because these cysts have occasionally shown malignant transformation. However, a high index of clinical suspicion is required to reach a diagnosis. We report a 68-year-old man complaining of a subcutaneous mass in his right buttock. Magnetic resonance imaging (MRI) showed a large cystic mass extending 25.7 cm from the pelvis to the buttock. Radiological features indicated a benign cystic tumor, but the level of serum carcinoembryonic antigen (CEA) (87.5 ng/mL) was increased. An incisional biopsy did not define the true histological nature of the lesion and was not useful for surgical planning. Although MRI could not detect malignant changes, the elevated serum CEA indicated malignant degeneration. The patient required a Miles operation for complete resection. Surgical pathology revealed focal areas of high-grade adenomatous and adenocarcinomatous changes in the cyst wall. After surgery, the serum CEA level decreased to below the normal range. The case presented here shows that early malignant degeneration of TGC is difficult to detect by MRI. Thus, a tailgut cyst should be completely removed, even if radiological examination cannot detect malignant features. Measurement of serum CEA may be helpful when the tumor expresses this antigen.

Hyporesponsiveness to natural killer T-cell ligand alpha-galactosylceramide in cancer-bearing state mediated by CD11b+ Gr-1+ cells producing nitric oxide.

CD1d-restricted natural killer T (NKT) cells are a potential therapeutic target for cancer, for which several clinical trials have already been reported. NKT cells are specifically activated by a synthetic glycolipid, alpha-galactosylceramide (alpha-GalCer). However, it is known that, in human cancer patients, NKT cells express a degree of hyporesponsiveness to alpha-GalCer. In this study, we have examined the mechanism by which hyporesponsiveness to alpha-GalCer can be induced. In cancer-bearing mice, alpha-GalCer-induced NKT cell expansion, cytokine production, cytotoxicity, and antimetastatic effect in vivo were all significantly impaired. In fact, alpha-GalCer could eliminate metastatic disease in naive animals but failed to protect cancer-bearing mice. CD11b(+) Gr-1(+) cells were particularly increased in cancer-bearing mice and were necessary and sufficient for the suppression of the alpha-GalCer response in a nitric oxide-mediated fashion. Administration of a retinoic acid to cancer-bearing mice reduced the population of CD11b(+) Gr-1(+) cells and effectively restored alpha-GalCer-induced protection. These results show a novel feature of NKT cell function in cancer. Furthermore, our data suggest a new strategy to enhance NKT cell-mediated anticancer immune responses by suppressing CD11b(+) Gr-1(+) cell functions.

[Informed consent for patients with pancreatic cancer].

Pancreatic cancer is an intractable malignancy with the poorest prognosis among digestive tract cancers. It is important when we obtain informed consent (IC) from patients with pancreatic cancer and their families to convey sufficiently that pancreatic cancer is intractable and provide support to help patients maintain a positive attitude toward treatment. Although the efficacy of chemo (radiation) therapy in pancreatic cancer is still unclear, the progress of various clinical trials on postoperative adjuvant therapy centered on gemcitabine hydrochloride, and chemo (radiation) therapy for unresectable tumors has raised expectations in recent years. To enable each individual patient to select the optimal treatment based on his or her personal outlook on life, it is important to obtain IC in good faith through the accurate diagnosis of pancreatic cancer and the use of the latest treatment information.

Identification of natural antisense transcripts involved in human colorectal cancer development.

Natural antisense transcripts (NATs) constitute a class of non-coding RNAs that have emerged as important regulators of gene expression. However, involvement of NATs in colorectal cancer (CRC) development has not been reported to date. In the present study, the up- and down-regulation of NATs were investigated in human CRC for their possible involvement in CRC development. Total RNAs isolated from 51 CRC tissues, 9 corresponding non-cancerous tissues and 19 liver metastatic tissues from surgically resected samples were subjected to expression analysis using a custom-microarray containing human sense/antisense probes for ca. 21,000 genes. Comparing CRC tissues with non-cancerous tissues, we identified 415 NATs differentially expressed in CRC and non-cancerous tissues to a significant degree (p<0.001, fold change >4.0 or ≤4.0). When a hierarchical clustering was performed on CRC and non-cancerous samples using these 415 NATs, the samples were separately clustered. Principal component analysis with the same NATs showed clear separation of CRC and non-cancerous samples using the first two principal components (PC1, 80%; PC2, 10%). To validate the expression results obtained from the microarray, the expressions of the 3 selected NATs were examined by strand-specific RT-qPCR, revealing that these expression profiles were consistent with those obtained from microarray analysis. In addition, the NAT expression patterns were found to be different between primary tumors with liver metastasis and those without liver metastasis. In conclusion, these findings taken together indicated that NATs identified in the present study would be involved in CRC development as well as possibly in its metastasis.

Impaired proliferative response of V alpha 24 NKT cells from cancer patients against alpha-galactosylceramide.

Human invariant V alpha 24(+) NKT cells are a relatively new subpopulation of lymphocytes. It has been reported that V alpha 24 NKT cells are significantly involved in some human diseases. We have evaluated the number and function of V alpha 24 NKT cells in both healthy volunteers and cancer patients. In this study we found that V alpha 24 NKT cells in unfractionated PBMCs obtained from cancer patients did not respond efficiently to alpha-galactosylceramide (alpha-GalCer) in vitro. Thus, their proportion after stimulation with alpha-GalCer was smaller than that found in healthy volunteers. However, the cancer patients' V alpha 24 NKT cells retained cytotoxic activity against malignant target cells, and they could efficiently proliferate to alpha-GalCer when fractionated by sorting. Furthermore, we found that addition of G-CSF to the culture could restore the low proliferative response of V alpha 24 NKT cells from cancer patients. These results suggest that some functions of NKT cells in cancer patients are impaired, and this observation carries significant implications for immunotherapy-based cancer treatments.