Nobuo Hoshi

Fatty Acid Synthase Is Expressed Mainly in Adult Hormone-sensitive Cells or Cells with High Lipid Metabolism and in Proliferating Fetal Cells1:

SUMMARY Animal fatty acid synthase (FAS) is a homodimer protein which synthesizes long-chain fatty acids and is rich in liver, brain, breast, and lung. However, the precise cellular localization of FAS in human tissues has not been elucidated. Immunohistochemistry with a new antibody to human FAS revealed that in adult human tissues FAS is distributed mainly in cells with high lipid metabolism (adipocytes, corpus luteum, hepatocytes, sebaceous glands, and Type II alveolar cells), in hormone-sensitive cells (anterior pituitary, apocrine gland, breast, endometrium, prostate, seminal vesicle, and adrenal cortex), and in a subset of epithelial cells of duodenum and stomach, colon absorptive cells, cerebral neurons, basket cells of cerebellum, decidua, uroepithelium, and epidymis. In fetal cells at 20 weeks of gestation, FAS was mainly present in proliferative epithelial cells of the digestive and respiratory systems, proximal renal tubules, adrenocortical cells, and mesenchymal and hematolymphoid cells. Staining was significant in nonproliferating cells, as observed in adult, and in sympathetic ganglion cells, Leidig cells of testis, and Langhans cells of chorionic villi. FAS is maintained in hormone-sensitive cells and/or cells active in lipid metabolism in the adult and is expressed in proliferating cells in the fetus, suggesting active fatty acid synthesis for energy utilization or membrane lipids.

h-Caldesmon in leiomyosarcoma and tumors with smooth muscle cell-like differentiation : Its specific expression in the smooth muscle cell tumor

h-Caldesmon (h-CD) is a protein combined with actin and tropomyosin that regulates cellular contraction. h-CD has been thought to be expressed exclusively in vascular and visceral smooth muscle cells (SMC). We examined h-CD expression immunohistochemically in tumors with SMC and SMC-like differentiation to clarify whether h-CD is specifically expressed in SMC tumors. The tumors examined in this study were six leiomyomas (LM), two angioleiomyomas (ALM), six leiomyosarcomas (LMS), eight rhabdomyosarcomas (RMS), eight malignant fibrous histiocytomas (MFH), four desmoids, three glomus tumors (GT), and two inflammatory myofibroblastic pseudotumors (IMP) of urinary bladder. We found that LM, ALM, LMS, and GT showed intense and extensive immunoreactivity for h-CD, whereas other tumors were completely negative for h-CD. In addition, h-CD was not present in the vascular pericytes and myofibroblasts, in contrast to actin. Although myoepithelial cells were immunopositive for h-CD, neoplastic myoepithelial cells of myoepithelial tumors and mixed tumors of the salivary gland and skin were all negative. These findings indicate that h-CD is a specific marker of both SMC and its neoplasms and that immunohistochemical detection of h-CD may facilitate the differential diagnosis between LMS and other tumors with SMC-like differentiation, including myofibroblastic tumors.

An Invasion-Independent Pathway of Blood-Borne Metastasis: A New Murine Mammary Tumor Model

It is generally believed that active invasion by cancer cells is essential to the metastatic process. In this report, we describe a murine mammary tumor (MCH66) model of metastasis that does not require invasion into the vascular wall of both the primary tumor and the target organ, in this case, the lung. The process involves intravasation of tumor nests surrounded by sinusoidal blood vessels, followed by intravascular tumor growth in the lung, without penetration of the vascular wall during the process. Comparative studies using a nonmetastatic MCH66 clone (MCH66C8) and another highly invasive metastatic cell line (MCH416) suggested that high angiogenic activity and sinusoidal remodeling of tumor blood vessels were prerequisites for MCH66 metastasis. Differential cDNA analysis identified several genes that were overexpressed by MCH66, including genes for the angiogenesis factor pleiotrophin, and extracellular matrix-associated molecules that may modulate the microenvironment toward neovascularization. Our analyses suggest that tumor angiogenesis plays a role in the induction of invasion-independent metastasis. This model should prove useful in screening and development of new therapeutic agents for cancer metastasis.

Morphological evidence for an invasion-independent metastasis pathway exists in multiple human cancers

BackgroundWe have previously described an alternative invasion-independent pathway of cancer metastasis in a murine mammary tumor model. This pathway is initiated by intravasation of tumor nests enveloped by endothelial cells of sinusoidal vasculature within the tumor. In this study, we examined whether evidence for the invasion-independent pathway of metastasis is present in human cancers.MethodsArchival specimens of 10 common types of human cancers were examined for the presence of sinusoidal vasculature enveloping tumor nests and subsequently generated endothelial-covered tumor emboli in efferent veins.ResultsA percentage of tumor emboli in all cancers was found to be enveloped by endothelial cells, but these structures were particularly prevalent in renal cell carcinomas, hepatocellular carcinomas and follicular thyroid carcinomas. A common feature of the vasculature in these tumors was the presence of dilated sinusoid-like structures surrounding tumor nests. A high mean vascular area within tumors, an indication of sinusoidal vascular development, was significantly related to the presence of endothelial-covered tumor emboli.ConclusionsThese results suggest that an invasion-independent metastatic pathway is possible in a wide variety of human cancers. Further investigation of this phenomenon may present new therapeutic strategies for the amelioration of cancer metastasis.

Myofibrosarcoma of the Bone: A Clinicopathologic Study

Myofibroblastic tumors are fairly recently established soft tissue neoplasms. Although most of them appear to be benign, myofibrosarcoma of the soft tissue, seemingly their malignant counterpart, have been reported. We describe the clinicopathologic and radiologic features of four cases of myofibrosarcoma arising from the bone. All but one of the patients were women ranging in age from 60 to 71 years. Two tumors occurred in the metaphyses of distal femurs and the others arose in the iliac bones. On radiologic examination all tumors exhibited well-demarcated lytic destructive lesions without periosteal reaction. Two tumors were localized in the bone, whereas the other two extended into surrounding soft tissues. Histologically, all tumors were composed principally of a mixture of a cell-rich fascicular area and a hypocellular fibrous area. In the former area tumor cells had rather eosinophilic spindle-shaped wavy cytoplasm and were arranged in interlacing fascicles and small storiform patterns with variable numbers of inflammatory cells. Tumors occasionally showed prominent pleomorphism, and large cells with hyperchromatic nuclei were seen. In contrast, hypocellular areas had various features, including collagenous, hyalinous scar-like and rarely keloid-like areas. Focal coagulation necroses were present in all but one tumor. Immunohistochemically, the tumors were positive for vimentin, muscle actin (HHF35), alpha-smooth muscle actin, calponin, and desmin, whereas all of them were negative for high molecular weight caldesmon. On follow-up there was one fatal case with distant metastases, whereas the clinical courses of other cases after wide resection were excellent. Myofibrosarcoma of the bone has distinctive histopathologic features, which should be distinguished from those of other bone tumors with myoid differentiation.

Epithelioid angiosarcoma of the intestinal tract with endothelin-1-like immunoreactivity

Two rare cases of intestinal epithelioid angiosarcoma arising in the sigmoid colon and small intestine are reported. The small intestinal tumours were located in the duodenum and upper jejunum. All tumours showed reddish-black protuberant masses with comparatively clear margins. Histology reveals solid and epithelioid growth of large polygonal cells, mimicking undifferentiated carcinoma. Vascular differentiation such as lumina containing red cells and intracytoplasmic vacuolization is noticed. Intense immunoreactivity toUlex europaeus agglutinin I and JC70 (CD31), and sporadic positive reaction to factor VIII related antigen were detected in one case but not in the other. However, both tumours have cells which show intense endothelin-1 immunoreactivity. Positive immunostaining occurred with low molecular weight keratins suggesting epithelial differentiation and suggested epithelioid angiosarcoma as a diagnosis, a specific entity within angiosarcoma. Because of their histological features, epithelioid angiosarcomas may be confused with undifferentiated carcinomas. Endothelin-1-like immunoreactivity seems to be a good marker for this type of angiosarcoma, even when the tumour cells lack usual marker substances for endothelial cells.

Overexpression of fatty acid synthase in human urinary bladder cancer and combined expression of the synthase and Ki-67 as a predictor of prognosis of cancer patients

To investigate the status of fatty acid synthase (FAS) in bladder tumors and evaluate its prognostic significance, we immunohistochemically examined the expression of FAS in normal urothelium, carcinoma in situ (CIS), and urothelial carcinoma (UC) in cystectomized bladder. In normal urothelium, only the surface layer expressed FAS, whereas the protein was detected in the basal layer or whole layer of CIS and UC in every specimen. Of the clinicopathological factors in UC, pathological tumor (pT) stage and histological grade were significantly correlated to FAS expression (P = 0.002, P < 0.0001, respectively). Univariate analysis for disease-specific survival indicated that the combination scores of FAS and Ki-67 expression, which were not associated with each other, was a more predictive variable than the individual score of each protein expression. Kaplan-Meier analysis showed that high combination scores of both proteins were significantly associated with poor prognosis (P = 0.04). In conclusion, FAS expression can be a biomarker for tumor aggressiveness and loss of differentiation of bladder cancer, and the evaluation of its expression level in combination with Ki-67 labeling index may be a precise predictor for poor prognosis of cancer patients.

Regular immunohistochemical localization of endothelin-1 and endothelin-B receptor in normal, hyperplastic and neoplastic human adrenocortical cells

The locallzation of endothelin (ET)‐l/blg ET‐1, ET‐3/big ET‐3, ET‐A and ET‐B receptor was Immunohistochemlcally examined in human adrenal glands composed of 36 normal cases, nine hyperplasla, 70 adenomas and seven carcinomas of cortical cells. In normal adrenals, ET‐1/blg ET‐1 and ET‐B receptor were regularly detected In the cortical cells, especially in the zona fasciculata for ET‐1 and zone glomerulosa for ET‐B receptor but not in the medulla, while ET‐A receptor localized occasionally in endothelial cells or rarely in cortical cells and ET‐3/blg ET‐3 was very limited In the cortical cells. In hyperplasia, adenoma and carcinoma, ET‐1 /big ET‐1 and ET‐B receptor showed frequent localization, although focal distrlbutlon of the ET‐B receptor was rather predominant in these groups. ET‐A receptor and ET‐3/big ET‐3 were very Infrequently expressed. Functioning versus non‐functioning and hypertensive versus normotenshe cases revealed no significant differences in the frequency of posltive cells for ET‐l /big ET‐1, ET‐3/big ET‐3, ET‐A receptor or ET‐B receptor. Alternatively, the frequency of lmmunoreactivtty to ET‐1/big ET‐1 or ET‐B receptor significantly decreased in hyperplasia, adenoma and carcinoma, when compared wlth that of normal adrenal cortex.

Frequent expression of 75 kDa nerve growth factor receptor and phosphotyrosine in human peripheral nerve tumours: an immunohistochemical study on paraffin-embedded tissues

One hundred and three benign, and 10 malignant peripheral nerve tumours were examined immunohistochemically for expression of 75 kDa nerve growth factor receptor (NGFR). In benign tumours NGFR was demonstrated at 61% in neurinoma, 71% in neurofibroma, 93% in neurofibromatosis and 90% in traumatic neuroma. Malignant neurogenic tumours were 100% positive for NGFR. Phosphotyrosine-immunoreactivity was detected in 76% of NGFR-positive tumours but the frequency of immunostained tumour cells was low. These results suggest that both benign and malignant peripheral nerve tumours express 75 kDa NGFR. The receptor seems to serve as growth signal transduction of the tumour cells in terms of phosphorylation of the tyrosine residue of the receptor or the target protein of the NGFR protein tyrosine kinase.

Expression of immunoreactivities to 75 kDa nerve growth factor receptor, trk gene product and phosphotyrosine in granular cell tumors

Nineteen granular cell tumors (GCT) of adults, two congenital granular cell epulides and five epulides fibrosae were immunohistochmically examined to detect the expression of 75 kDs nerve growth factor receptor (NGFR), frk gene product, phasphotyrosine (PT), protein gene product 9.5 (PGP9.5) and S‐100 protein. The NGFR‐immunoreactivity (IR) and trk gene product‐IR were expressed on almost all granular cells of GCT. PT‐IR was also demonstrated on granular calls of all GCT examined, although the frequency of positive cells was low. Congenital granular celi epulides and epulldes fibrosae were negative for NGFR‐IR, trk gene product‐IR and PT‐IR. S‐100 protein was localized in granular cells of adult GCT but not in the granular cells of congenital epulis. On the other hand, PGP9.5 was detected in granular cells of both conditions and in fibroblastic cells of epulis fibrosa. The present results further indicate that GCT is of peripheral nerve Schwann cell origin, while the congenital granular cell epulides are not of neural origin. NGFR and trk gene product expressed on GCT seems to be functional in terms of phosphorylation of the tyrosine residue in the receptor or downstream protein in signal transduction.