Hiroyuki Hatanaka

Neuropilin 1 and neuropilin 2 co-expression is significantly correlated with increased vascularity and poor prognosis in nonsmall cell lung carcinoma.

Cell‐retained isoforms of vascular endothelial growth factor A (VEGF‐A) have been reported to play an essential role in tumor progression through stromal neovascularization in malignant solid tumors. While more than 95% of nonsmall cell lung carcinoma (NSCLC) expresses cell‐retained VEGF‐A isoform, the clinicopathologic implications of neuropilin (NRP), considered the specific receptor for limited types of VEGF‐A isoform, are not well understood.

Thrombospondin 2 expression is correlated with inhibition of angiogenesis and metastasis of colon cancer

SummaryTwo subtypes of thrombospondin (TSP-1 and TSP-2) have inhibitory roles in angiogenesis in vitro, although the biological significance of these TSP isoforms has not been determined in vivo. We examined TSP-1 and TSP-2 gene expression by reverse transcription polymerase chain reaction (RT-PCR) analysis in 61 colon cancers. Thirty-eight of these 61 colon cancers were positive for TSP-2 expression and showed hepatic metastasis at a significantly lower incidence than those without TSP-2 expression (P = 0.02). TSP-2 expression was significantly associated with M0 stage in these colon cancers (P = 0.03), whereas TSP-1 expression showed no apparent correlation with these factors. The colon cancer patients with TSP-2 expression showed a significantly low frequency of liver metastasis correlated with the cell-associated isoform of vascular endothelial growth factor (VEGF-189) (P = 0.0006). Vascularity was estimated by CD34 staining, and TSP-2(–)/VEGF-189(+) colon cancers showed significantly increased vessel counts and density in the stroma (P < 0.0001). TSP-2(–)/VEGF-189(+) colon cancer patients also showed significantly poorer prognosis compared with those with TSP-2(+) / VEGF-189(–) (P = 0.0014). These results suggest that colon cancer metastasis is critically determined by angiogenesis resulting from the balance between the angioinhibitory factor TSP-2 and angiogenic factor VEGF-189.

Clinical implications of interleukin (IL)-10 induced by non-small-cell lung cancer

BACKGROUND The type 2 cytokine interleukin (IL)-10 has been reported to inhibit the antitumour activity of the regional immunity against various neoplasms. Certain lung cancers produce IL-10, but the clinical significance of IL-10 expression is not well understood. PATIENTS AND METHODS We examined IL-10 and IL-10 receptor (IL-10R) mRNA expression in 82 non-small-cell lung cancers (NSCLC) by reverse transcription-polymerase chain reaction (RT-PCR) assay. Immunohistochemistry (IHC) and enzyme immunoassay (EIA) were applied to evaluate the cellular localisation and the serum levels of IL-10. RESULTS RT-PCR assay revealed IL-10 mRNA expression in 68 (83%) of 82 NSCLC surgical specimens (40 of 50 adenocarcinomas, 22 of 26 squamous cell carcinomas, 5 of 5 large-cell carcinomas, 1 of 1 adenosquamous-cell carcinoma). RT-PCR assay also revealed IL-10R mRNA expression in 79 cases of NSCLC (96.1%). IL-10 expression was confirmed within tumour cells by IHC. EIA showed no significant serum IL-10 elevation in the 12 NSCLC positive for IL-10 mRNA expression (0-2.99 pg/ml). The NSCLC patients with IL-10 production showed significantly poorer prognosis than those without IL-10 production (P < 0.05, Kaplan Meier, log-rank test). CONCLUSIONS These results suggested that the cytoplasmic IL-10 correlated to clinical prognosis, and that IL-10 expression is a prognostic factor for NSCLC.

Multidrug resistance-associated protein (MRP) expression is correlated with expression of aberrant p53 protein in colorectal cancer

Multidrug resistance-associated protein (MRP) is one of the major factors responsible for non-P-glycoprotein (Pgp)-mediated multidrug resistance of human tumour cells. In this study, we examined MRP and aberrant p53 expression in 54 colorectal cancers (CRC), 35 carcinoma in adenomas (CIA) and 40 adenomatous polyps by immunohistochemical procedures. 38 of 54 (70%) CRCs, 16 of 35 (46%) CIAs and 3 of 40 (8%) adenomatous polyps were MRP positive (chi 2 test, P < 0.0001). 36/54 (67%) CRCs, 10/35 (29%) CIAs and 0/40 adenomatous polyps were p53 positive. 30 of the 36 p53-positive CRCs were also MRP positive and 8/10 CIAs were both p53 and MRP positive. MRP overexpression correlated with aberrant p53 accumulation in CRCs and CIAs (chi 2 test, P < = or 0.01). Coexpression of MRP and p53 in the same cells was confirmed in the CRCs and CIAs by double staining procedures. These results suggested that MRP overexpression is related to aberrant p53 expression in CRC.

Serum Levels of Vascular Endothelial Growth Factor and Cavity Formation in Active Pulmonary Tuberculosis

Background: In active pulmonary tuberculosis, certain cytokines have been postulated to be related to cavity formation, although the detailed mechanism of cavity formation is not yet known. Objective: We examined the relationship between cavity formation in pulmonary tuberculosis and vascular endothelial growth factor (VEGF), which functions as an angiogenesis factor. Methods: Forty-eight patients with active pulmonary tuberculosis were divided into two groups according to cavity formation as evaluated by chest high-resolution computed tomography. We evaluated serum VEGF levels by enzyme immunoassay. Results: Group A (with cavities) was comprised of 22 patients and group B (without cavities) was comprised of 26 patients. The serum levels of VEGF were significantly higher in group B (58.733 ± 21.612 pg/ml) than those in normal individuals (8.739 ± 3.656 pg/ml) and in group A (13.053 ± 8.670 pg/ml) (Mann-Whitney U test, p = 0.0149 and p = 0.0481, respectively). Serum levels of interleukin-8 and tumor necrosis factor-α were not significantly different between the two groups. Conclusion: These findings suggested that increased serum VEGF levels subdue cavity formation in active pulmonary tuberculosis.

Growth Stimulation of Non-small Cell Lung Cancer Xenografts by Granulocyte-macrophage Colony-stimulating Factor (GM-CSF)

Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been suggested to be involved in the carcinogenesis of some types of tumours by autocrine or paracrine mechanisms. We examined GM-CSF/GM-CSF receptor (GM-CSFR) gene expression in 20 human non-small cell lung cancer (NSCLC) xenografts. The stimulatory effects of GM-CSF were examined using GM-CSF transgenic severe combined immunodeficient (SCID) mice (GM-Tg-SCID), which produce abundant human GM-CSF. A NSCLC xenograft (LC11-JCK), expressed GM-CSFR but not GM-CSF, and showed more rapid growth in GM-Tg-SCID than non-GM-CSF transgenic SCID mice (non-Tg-SCID). GM-CSF gene expression was detected in 48 of 90 (53%) primary NSCLC human specimens and GM-CSFR gene expression was detected in 42 specimens (47%). GM-CSF expression was detected in 13 of 30 squamous cell carcinoma specimens (43%) and GM-CSFR expression was detected in 10 specimens (33%). Patients with squamous cell carcinoma coexpressing GM-CSF and GM-CSFR showed significantly poorer prognosis than those expressing neither GM-CSF nor GM-CSFR (P < 0.05, Cox-Mantel test). These results suggest that GM-CSF can have a stimulatory effect on some NSCLC.

Bronchial carcinoid tumor with gangliocytic- and paraganglionlike differentiation

neuroendocrine tumors of the lung show a spectrum of histological variations ranging from classic carcinoid tumors to small-cell carcinoma [1]. We encountered a case of bronchial “carcinoid tumor with gangliocyticand paraganglionlike differentiation.” A 65-year-old man was admitted due to an abnormal shadow on his chest radiograph. He was asymptomatic, but a well-circumscribed coin lesion was seen in the right upper lung field. He underwent right upper lobectomy and dissection of mediastinal lymph nodes. Examination of the digestive tract, including abdominal computed tomography, duodenography, and barium enema, showed no apparent abnormalities. No hormonal signs or symptoms were recorded. The 25×18 mm polypoid tumor involving the right upper lobe bronchus was well demarcated, and its cut surface was yellow or yellowish-white in color (Fig. 1). No necrotic foci were seen in the tumor. The tumor was composed of two different parts, containing three types of tumor cells. The major part of the tumor showed the trabecular, papillary and ribbonlike arrangement of medium-sized neoplastic cells, typical of carcinoid tumor (Fig. 2a). The polygonal to cuboidal cells contained round to ovoid nuclei. Nuclear atypia was minimal. The cells were focally arranged in rosettes. Mitotic figures were not seen. Some regions of the tumor showed proliferation of large round cells similar to ganglion cells surrounded by smaller spindle-shaped cells and fibrillary components (Fig. 2b). The ganglionlike cells possessed plump eosinophilic cytoplasm and vesicular nuclei with prominent nucleoli. The cells were embedded in fibrillar tissue somewhat resembling the nervous tissue. The neoplastic tissue showed transitional or mixed features. No regional lymph nodes were involved histologically. Histochemically, abundant argyrophilic granules were observed in the cytoplasm of both the carcinoidlike and smaller paraganglionlike tumor cells (Fig. 2c, d). Ganglionlike cells were only mildly argyrophilic. The immunohistochemical findings are summarized in Table 1. Some of the carcinoid cells and the smaller paraganglionlike cells were immunoreactive for chromogranin A, and these cells were mostly argyrophilic. The ganglionlike cells were negative for chromogranin A. While most carcinoid cells were weakly positive for synaptohysin in the cytoplasm (Fig. 2e), the ganglionlike cells were strongly