Hye-Jeong Choi

Tristetraprolin regulates expression of VEGF and tumorigenesis in human colon cancer

Tristetraprolin (TTP) is an AU‐rich element‐binding protein that regulates mRNA stability. Here, we report that TTP suppress the growth of human colon cancer cells both in vivo and in vitro by regulating of the expression of vascular endothelial growth factor (VEGF). TTP protein expression in human colonic tissues was markedly decreased in colonic adenocarcinoma compared with in normal mucosa and adenoma. VEGF expression was higher in colonic adenocarcinoma than in normal mucosa and adenoma. Specific inhibition of TTP expression by RNA‐interference increased the expression of VEGF in cultured human colon cancer cells, and TTP overexpression markedly decreased it. In addition, elevated expression of TTP decreased the expression level of luciferase linked to a 3′ terminal AU‐rich element (ARE) of VEGF mRNA. Colo320/TTP cells overexpressing TTP grew slowly in vitro and became tumors small in size when xenografted s.c into nude mice. These findings demonstrate that TTP acts as a negative regulator of VEGF gene expression in colon cancer cells, suggesting that it can be used as novel therapeutic agent to treat colon cancer.

Thoracic Splenosis: A Case Report and the Importance of Clinical History

We present a case of thoracic splenosis in a 42-yr-old man with a medical history of abdominal surgery for a penetration injury with an iron bar of the left abdomen and back. He had been in good condition, but a chest radiograph taken during a regular checkup showed a multinodular left pleura-based mass. Computed tomography (CT) showed that the mass was well-enhanced and homogeneous, indicating a sclerosing hemangioma. Following its removal by video-assisted thoracoscopic surgery, the mass appeared similar to a hemangioma, with marked adhesion to the left side diaphragmatic pleura and lung parenchyma. Frozen section showed that the lesion was a solid mass consisted with abundant lymphoid cells, suggesting a low grade lymphoma. On permanent section, however, the mass was found to be composed of white pulp, red pulp, a thick capsule and trabeculae and was diagnosed as ectopic splenic tissue, or thoracic splenosis. Review of the patients history and chest CT at admission revealed that the patient had undergone a splenectomy for the penetration injury 20 yr previously.

Intratumorally Establishing Type 2 Innate Lymphoid Cells Blocks Tumor Growth

A long-standing question in the field of tumor immunotherapy is how Th2 cytokines block tumor growth. Their antitumor effects are particularly prominent when they are secreted continuously in tumors, suggesting that Th2 cytokines may create a tumor microenvironment unfavorable for tumor growth independently of adaptive immunity. In this study, we show that local production of IL-33 establishes a high number of type 2 innate lymphoid cells (ILC2s) with potent antitumor activity. IL-33 promotes secretion of a massive amount of CXCR2 ligands from ILC2s but creates a tumor microenvironment where tumor cells express CXCR2 through a dysfunctional angiogenesis/hypoxia/reactive oxygen species axis. These two signaling events converge to reinforce tumor cell–specific apoptosis through CXCR2. Our results identify a previously unrecognized antitumor therapeutic pathway wherein ILC2s play a central role.

Depletion of Alloreactive T-Cells by Anti-CD137-Saporin Immunotoxin

Depletion of alloreactive T-lymphocytes from allogeneic bone marrow tansplants may prevent graft-versus-host disease (GVHD) without impairing donor cell engraftment, immunity, and the graft-versus-leukemia (GVL) effect. Alloreactive T-cells may be identified by their expression, upon activation, of CD137, a costimulatory receptor and putative surrogate marker for antigen-specific effector T-cells. In this context, we tested the use of anti-CD137-saporin immunotoxin to selectively deplete mouse and human alloreactive T-cells. Anti-CD137 antibodies were internalized by cells within 4 h of binding to the cell surface CD137, and anti-CD137-saporin immunotoxin effectively killed polyclonally activated T-cells or antigen-stimulated T-cells. Transfer of donor T-cells after allodepletion with anti-CD137-saporin immunotoxin failed to induce any evident expression of GVHD; however, a significant GVL effect was observed. Targeting of CD137 with an immunotoxin was also effective in killing polyclonally activated or alloreactive human T-cells. Our results indicate that anti-CD137-saporin immunotoxin may be used to deplete alloreactive T-cells prior to bone marrow transplantation and thereby prevent GVHD and the relapse of leukemia.

Roles of Host Nonhematopoietic Cells in Autoimmunity and Donor Cell Engraftment in Graft-versus-host Disease.

Background Graft-versus-host disease (GVHD) is initiated when alloreactive donor T cells are primed by host APCs to undergo clonal expansion and maturation. Since there is a controversy regarding the role of nonhematopoietic cells in GVHD, we wanted to investigate the influence of MHC disparity on nonhematopoietic cells on the pathogenesis of GVHD in the MHC-haplomismatched C57BL/6 (H-2b) or DBA/2 (H-2d)→unirradiated (C57BL/6×DBA/2) F1(BDF1; H-2b/d) murine model of acute GVHD (aGVHD) or chronic GVHD (cGVHD). Methods We generated (BDF1→C57BL/6), (BDF1→DBA/2), and (BDF1→BDF1) chimeras and examined GVHD-related parameters and donor cell engraftment in those chimeras. Results Using this experimental system, we found that 1) severe aGVHD across MHC Ag barrier depends on the expression of nonhematopoietically rather than hematopoietically derived alloAgs for maximal GVHD manifestations; 2) host APCs were sufficient to break B cell tolerance to self molecules in cGVHD, whereas host APCs were insufficient to induce autoimmunity in aGVHD; 3) donor cell engraftment was greatly enhanced in the host with MHC-matched nonhematopoietic cells. Conclusion Taken together, our results provide an insight into how MHC disparity on GVHD target organs contribute to the pathogenesis of GVHD.

Pituitary Carcinoma with Mandibular Metastasis: A Case Report

Pituitary carcinomas are rare primary adenohypophyseal tumors with cerebrospinal or extracranial metastasis. The present case, the first report of the disease in Korea, involved a 36-yr-old woman who presented with a 3-week history of headache. Brain magnetic resonance imaging revealed a 2.5-cm sellar and suprasellar mass showing heterogeneous enhancement with suspicious invasion of both cavernous sinuses. The patient underwent gross-total resection. The tumor cells were composed of polygonal cells singly or in variable-sized nests. The nuclei were large and round with prominent nucleoli. The cytoplasms was acidophilic and granular. Marked pleomorphism and frequent mitoses (3 per 10 HPFs) were found. By immunohistochemistry, tumor cells were strongly positive for prolactin, but negative for ACTH and GH. Additional immunostainings for cytokeratin, vimentin, and glial fibrillary acidic protein (GFAP) were negative. After the surgery, the patient received radiotherapy because of the atypical histologic features. The prolactin level fell from 123.17 ng/mL to 5.17 ng/mL after surgery. Nine months after the initial diagnosis, the patient died from mandibular metastasis associated with the pituitary carcinoma.

Concurrent Gastric Adenocarcinoma of Fundic Gland Type and Carcinoma with Lymphoid Stroma: A Rare Case Report.

Both gastric adenocarcinoma of fundic gland type (ADC-FG) and carcinoma with lymphoid stroma (lymphoepithelioma-like carcinoma, LELC) are relatively rare. Epstein-Barr virus (EBV) has been implicated in the pathogenesis of LELC. However, the pathogenesis of ADC-FG, as well as the role of EBV in the carcinogenesis of LELC, remain unclear and under debate. The current study presents a case of concurrent ADC-FG and LELC in the stomach in a 69-year-old man. Total gastrectomy was performed, and two separate masses were identified. Upon histological and immunohistochemical examination, the mass located in the lower body was determined to be LELC and the mass in the upper body was diagnosed as ADC-FG. The lesions were characterized by different mucin phenotypes and EBV in situ results. In the lower-body mass, EBV in situ hybridization expression was diffusely strongly positive, but MUC2, MUC5AC, MUC6, and CD10 were all negative. On the other hand, in the upper-body mass, the results were positive for MUC6 but negative for MUC2, MUC5AC, CD10, and EBV by in situ hybridization. The remaining gastric tissue was unremarkable, and perigastric lymph node metastases were absent. Seven months after the gastrectomy, a postoperative computed tomography scan revealed no recurrence or metastasis.