Michael B. Nicholl

Sirtuin 1 in malignant transformation: Friend or foe?

In the past decade, great interest has been shown in the role of sirtuin 1 (SIRT1) in tumorigenesis. The published data show SIRT1 can function as both a tumor promoter and tumor suppressor. In this review, we summarize the available data regarding the role of SIRT1 in tumorigenesis, with a focus on the potential mechanisms. The seemingly controversial role of SIRT1 in tumorigenesis suggests that SIRT1 might play a dual role in different tissue contexts depending on the temporal and special distribution of different SIRT1 upstream and downstream factors. Clearly, the role of SIRT1 in tumorigenesis is poorly understood and more research is necessary to elucidate its function in the malignant process.

Resveratrol enhances radiation sensitivity in prostate cancer by inhibiting cell proliferation and promoting cell senescence and apoptosis.

Radiation therapy (XRT) for treatment of localized prostate cancer (PCA) has outcomes similar to surgery and medical therapy. Toxicities of XRT and the relative radioresistance of PCA limit the effectiveness of this treatment method. Safe and effective radiosensitizing agents are lacking to enhance the effectiveness for XRT for PCA. In this study, the effect of XRT in combination with the radiosensitizing agent resveratrol (RSV) was investigated in a radioresistant PCA cell line, PC‐3. Our results show the addition of RSV to XRT (XRT/RSV) synergistically enhanced XRT‐induced apoptosis and inhibition of PC‐3 proliferation. The antiproliferative effect of XRT/RSV treatment correlated with increased expression of p15, p21, and mutant p53 and decreased expression of cyclin B, cyclin D, and cdk2. Increased apoptosis correlated with increased expression of Fas and TRAILR1. Furthermore, XRT/RSV had little effect on the expression of p‐AKT, whereas it increased the expression level of p‐H2A.X, a marker for senescence. These data highlight the potential of RSV as a radiation sensitizer for PCA treatment and warrant further investigation. (Cancer Sci 2012; 103: 1090–1098)

A Possible Role for Perforin and Granzyme B in Resveratrol‐Enhanced Radiosensitivity of Prostate Cancer

Perforin and granzyme B are expressed primarily by activated lymphocytes (cytotoxic T cells, natural killer cells, and natural killer T cells) and function together to induce apoptosis of target cells. Typically, these proteins are not expressed in tumor cells. In the present study, we established the constitutive expression of perforin and granzyme B by the PC-3 and DU145 prostate cancer (PCA) cell lines with reverse transcription polymerase chain reaction, immunohistochemistry, Western blot, or a combination of techniques. The combination of radiation and resveratrol (XRT/RSV) additively/synergistically decreased survival of PCA because, at least in part, of increased apoptosis. We further demonstrated that treatment with RSV up-regulated the expression of both perforin and granzyme B, whereas treatment with XRT up-regulated the expression of granzyme B, but not that of perforin. Combined XRT/RSV treatment of PCA cells further increased the expression of both perforin and granzyme B compared with RSV or XRT alone. Thus, increased radiosensitivity of prostate cancer cells induced by RSV correlated with up-regulation of perforin and granzyme B, demonstrating a possible mechanism for tumor apoptosis. These findings might be helpful in devising new strategies for treating PCA.

IL-35 promotes pancreas cancer growth through enhancement of proliferation and inhibition of apoptosis: Evidence for a role as an autocrine growth factor

Interleukin-35 (IL-35), an IL-12 cytokine family member, mediates the immune inhibitory function of regulatory T cells (Treg). We assayed the presence of IL-35 in paraffin-embedded human pancreas cancer (PCAN) and unexpectedly found IL-35 was expressed mainly by epithelial derived PCAN cells, but not by Treg. We further examined the expression and effect of exogenous IL-35 in human PCAN cell lines and found IL-35 promoted growth and inhibited apoptosis in PCAN cell lines. IL-35 induced proliferation correlated with an increase in cyclin B, cyclin D, cdk2, and cdk4 and a decrease in p27 expression, while inhibition of apoptosis was associated with an increase in Bcl-2 and a decrease in TRAILR1. We conclude IL-35 is produced by PCAN in vivo and promotes PCAN cell line growth in vitro. These results might indicate an important new role for IL-35 as an autocrine growth factor in PCAN growth.

IL‐9 inhibits HTB‐72 melanoma cell growth through upregulation of p21 and TRAIL

IL‐9 is a pleiotropic cytokine produced mainly by Th9 cells. IL‐9 may have an anti‐proliferative role in murine melanoma, however, its effect on human melanoma is unknown.

IL-32α has differential effects on proliferation and apoptosis of human melanoma cell lines.

Interleukin‐32 (IL‐32) is a recently recognized intracellular, proinflammatory cytokine which may play a role in cancer metastasis and patient survival. The role of IL‐32 in cancer, especially its direct effect on cancer cells, is not well understood.

Case Report of Pancreatic Dermoid Cyst: Can Fine Needle Aspiration Make the Diagnosis?

CONTEXT Pancreatic dermoid cysts are rare, benign, germ cell tumors and part of the differential diagnosis for cystic neoplasms of the pancreas. CASE REPORT A 35-year-old man presented with an incidentally discovered, 2 cm cystic pancreatic neoplasm of the pancreatic tail identified on CT scan. Endoscopic ultrasound (EUS) revealed a complex, honeycomb lesion. Fine needle aspiration (FNA) yielded a sample of whitish, necrotic material containing histiocytes, benign epithelial cells, and lymphocytes. After distal pancreatectomy and splenectomy was performed, histology revealed a cyst lined by stratified squamous epithelium with benign sebaceous units consistent with a pancreatic dermoid cysts. DISCUSSION Although axial imaging reliably detects cystic neoplasms of the pancreas, diagnostic criteria for rare lesions are lacking; therefore alternative modalities such as EUS/FNA can be utilized. This case report highlights the EUS and FNA findings associated with pancreatic dermoid cysts.

IL-33 acts as a foe to MIA PaCa-2 pancreatic cancer

IL-33 is a member of the IL-1 family of cytokines, and no study has been performed to address its direct anti-tumor effect. This study is designed to investigate whether IL-33 has any direct effect on pancreatic cancer. Clonogenic survival assay, immunohistochemistry, TUNEL staining, proliferation, caspase-3 activity kits and RT-PCR were used to evaluate the effects of IL-33 on cell survival, proliferation and apoptosis of a pancreatic cancer cell line, MIA PaCa-2. We found that the percentage of colonies of MIA PaCa-2 cells, PCNA+ cells and the OD value of cancer cells were all decreased in the presence of IL-33. TUNEL+ cells and the relative caspase-3 activity in cancer cells were increased in the presence of IL-33. We further found that its anti-proliferative effect on cancer cells correlated with downregulation of pro-proliferative molecules cdk2 and cdk4 and upregulation of anti-proliferative molecules p15, p21 and p53. Its pro-apoptotic effect correlated with downregulation of anti-apoptotic molecule FLIP and upregulation of pro-apoptotic molecule TRAIL. These results suggest that IL-33 presents significant anti-tumor effects by inhibition of proliferation and induction of apoptosis of MIA PaCa-2 pancreatic cancer cells. Thus, strength of IL-33/ST2 signal pathway might be a promising way to treat pancreatic cancer.

Unveil the mysterious mask of cytokine-based immunotherapy for melanoma

Melanoma is the leading cause of death among all skin cancers and its incidence continues to rise rapidly worldwide in the past decades. The available treatment options for melanoma remain limited despite extensive clinical research. Melanoma is an immunogenic tumor and great advances in immunology in recent decades allow for the development of immunotherapeutic agents against melanoma. In recent years, immunotherapy utilizing cytokines has been particularly successful in certain cancers and holds promise for patients with advanced melanoma. In this review, an overview of the current status and emerging perspectives on cytokine immunotherapy for melanoma are discussed in details. Such a study will be helpful to unveil the mysterious mask of cytokine-based immunotherapy for melanoma.

Repeat PEG placement is safe for head and neck cancer patients

PURPOSE Percutaneous endoscopic gastrostomy (PEG) provides durable nutritional access for head and neck (HNC) patients as they undergo treatment. Continuing treatment of HNC may necessitate repeat PEG placement. We report our outcomes with repeat PEG compared to first-time PEG in HNC patients. MATERIALS AND METHODS A retrospective chart review identified morbidity, mortality, and possible risk factors for complications. RESULTS Repeat PEG tubes constituted 17% of PEG procedures. Morbidity was rare and similar complication rates were found between the initial PEG and repeat PEG groups (2% vs. 11%, p=0.131). There were no mortalities. CONCLUSIONS Repeat PEG plays an important role in the care of HNC patients and can be considered a safe means to establish durable enteric feeding access for patients with recurrent cancer or treatment complications.