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Matrix metalloproteinases (MMPs) are believed to play an essential role in cancer invasion, although detailed differences between noninvasive and invasive lung carcinomas are still unclear. To elucidate the expression and activity patterns of MMPs in noninvasive and invasive carcinoma of the lung, we performed in situ hybridization and real-time reverse transcription-polymerase chain reaction to detect messenger RNAs (mRNAs) of MMPs and their tissue inhibitors (TIMPs). The basement membrane was evaluated by immunohistochemistry for type IV collagen. Gelatinase activity was examined by zymography and in situ zymography. A total of 14 surgically resected primary pulmonary adenocarcinomas were used for this study. All the tumors were adenocarcinoma mixed bronchioloalveolar carcinomas according to the 1999 WHO classification. MMP and TIMP2 mRNAs were detected by in situ hybridization in all samples, in both noninvasive and invasive carcinoma components. Signals for MMP mRNAs were significantly higher in both noninvasive and invasive carcinomas than in tumor-free lung tissue. However, the differences were small between noninvasive and invasive carcinomas, not only in the amount of mRNA but also in the activity of the MMPs. In most carcinomas, stromal fibroblast-type cells tended to express levels of MMP and TIMP2 mRNAs that were higher than or at least similar to those expressed in epithelial cells. Our data on mixed adenocarcinoma suggest that noninvasive carcinoma areas already express a molecular mechanism involving MMPs similar to that expressed by invasive carcinoma areas. Stromal fibroblast-type cells seem to be the most important source of MMPs, from the earliest event of tumor invasion by pulmonary adenocarcinomas.

We report a case of granulocyte-colony stimulating factor (G-CSF) producing urothelial carcinoma of the renal pelvis in a 39-year old man. The patient was admitted to Kobe University Hospital, Kobe, Japan, complaining of macrohematuria and a 6-month history of left abdominal swelling. Abdominal computed tomography showed a large mass in the left kidney and para-aortic lymph node enlargement. A remarkable degree of leukocytosis was detected without any acute infectious disease. Enzyme immunoassay of the serum demonstrated a remarkable high concentration of G-CSF. The patient underwent left nephroureterectomy and para-aortic lymphadenectomy. Histochemical examination revealed urothelial carcinoma. Immunohistochemical staining with an anti-G-CSF antibody demonstrated G-CSF secreting cells. The patient died 8 weeks after the surgical operation. To our knowledge, this is the second case of G-CSF producing urothelial carcinoma of renal pelvis reported in the English literature.

Hyaluronan (HA) is thought to play several important roles in tumor growth, tumorigenicity, and tumor dissemination and metastasis. Recently, three isoforms of hyaluronan synthase (HAS) have been cloned. Our objective was to determine which of the HAS isoforms were expressed in pleural malignant mesotheliomas, the most representative lesion of HA-producing tumors. We studied 10 cases of pleural malignant mesothelioma using novel antibodies of HAS. We compared HAS expression patterns of mesothelioma and pulmonary adenocarcinoma. Immunohistochemically, 9 of 10 (90%) cases of mesothelioma had extensive reaction to anti-HAS1 and anti-HAS2 antibodies, while HAS3 overexpression was present in 4 of 10 cases (40%). Of 20 cases of pulmonary adenocarcinoma, 5 overexpressed HAS1 (25%), 16 of 20 HAS2 (80%), and 4 of 20 HAS3 (20%). The expression level of HAS1 was significantly higher in mesotheliomas than in pulmonary adenocarcinoma (P=0.0036). Our data suggests that HAS1 might be a useful positive marker of malignant mesothelioma. However, a definitive conclusion should be based on further large-scale studies.

Background: DNA damage sensor proteins have received much attention as upstream components of the DNA damage checkpoint signaling pathway that are required for cell cycle control and the induction of apoptosis. Deficiencies in these proteins are directly linked to the accumulation of gene mutations, which can induce cellular transformation and result in malignant disease., Methods: Using 48 sets of tumor tissue specimens and peripheral normal lung tissue specimens from 48 patients with nonsmall cell lung carcinoma (NSCLC) who underwent surgery, the authors investigated the expression of hRad9 protein, a member of the human DNA damage sensor family, using immunohistochemical and Western blot analyses., Results: Immunohistochemical analysis detected the accumulation of hRad9 in the nuclei of tumor cells in 16 tumor tissue specimens, (33% of tumor tissue specimens examined). Western blot analysis also revealed elevated levels of phosphorylated hRad9 protein in NSCLC cells that was accompanied by the detection of phosphorylated Chk1, a protein kinase that regulates the downstream signaling of the DNA damage checkpoint pathway. Furthermore, strong expression of hRad9 was correlated with an increase in Ki-67 expression index in the tumor cells that were examined., Conclusions: The findings made in the current study suggest that Rad9 expression may play an important role in cell cycle control in NSCLC cells and may influence NSCLC cell phenotype.

We report the case of a female patient with bilateral metachronous adrenocortical cancer who survived long-term after adrenalectomy. In 1991, the patient underwent left adrenalectomy to remove a huge adrenal mass (10 x 9 cm) displaying no hormonal abnormality. Histological diagnosis was adrenocortical cancer. A right adrenal mass (7 x 6 cm) was found 4 years after left adrenalectomy. Right adrenalectomy was performed, and histological diagnosis was again adrenocortical cancer. The patient remains alive with no evidence of disease 8 years after last surgery.

Oncocytic adrenocortical carcinoma is rare. To our knowledge, only 6 cases have been previously reported. We describe an additional case of oncocytic adrenocortical carcinoma. A 54-year-old man presented with a right subcostal mass. Computed tomography demonstrated a massive tumor in the right abdomen. Because renal or adrenal cancer was suspected, right adrenalectomy and nephrectomy were performed. Histologic examination revealed an oncocytic adrenocortical carcinoma. Five months postoperatively, multiple metastases had developed and were treated with surgical resection, chemotherapy, vascular embolization, and radiotherapy. At last follow-up, the patient was alive with pulmonary and adrenal metastases and undergoing treatment with mitotane.

Neuroendocrine tumors of the lung comprise a heterogeneous group of tumors that represents a spectrum of disease from typical carcinoid tumors to the high-grade neuroendocrine carcinomas (large-cell neuroendocrine carcinomas and small-cell carcinomas). The high-grade neuroendocrine carcinomas are characterized by early metastasis and poor prognosis. The peripheral location and especially the massive pleural spread are rare for a high-grade neuroendocrine carcinoma. We report a case in which a high-grade neuroendocrine carcinoma, associated with dermatomyositis, presented an unusual pattern of progression, mimicking malignant pleural mesothelioma on diagnostic imaging.

Background: More than 80% of patients with advanced prostate cancer have skeletal involvement, but the biology of bone metastasis is poorly understood. This study investigated the in vivo formation and progression of bone metastases under conditions that resembled the human bone environment as closely as possible., Methods: Adult human bone fragments were implanted subcutaneously into 120 male NOD/SCID mice. Four weeks later, 1 x 10(7) LNCaP prostate cancer cells or phosphate-buffered saline were injected intravenously into 80 or 40 mice, respectively. The implanted bone fragments were removed from 20 to 10 mice in each group at 2, 4, 6, and 8 weeks after injection., Results: LNCaP colonized the bone marrow blood vessels within 2 weeks, and then gradually expanded into the entire medullary cavity. An osteoblastic response often occurred at the edges of metastatic foci (intertrabecular bone metaplasia). In addition, new bone formation was observed adjacent to mature lamellar bone (appositional bone formation). These two processes appeared to occur through different mechanisms, but might similarly cause osteosclerosis. Osteoclasts showed a marked increase in numbers at sites of early tumor invasion, whereas few osteoclasts were observed at sites where tumor invasion was complete., Conclusions: The predominance of osteoblastic change with resorption may lead to bone remodeling in metastatic lesions, and osteoclasts may play an important role in bone metastasis from prostate cancer., (Copyright 2003 Wiley-Liss, Inc.)

Objectives: Injury causes the disruption of homeostatic cell-cell interactions and epithelial regeneration is part of the threshold response. Due to the lack of a good animal model for the investigation of these mechanisms, the kinetics of cell proliferation after injury to the human respiratory tract are poorly understood., Methods: To create a better model of human bronchioloalveolar epithelial regeneration, we engrafted adult human lung tissue into nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Then the lung tissue was studied at various times up to 20 weeks after implantation., Results: The xenografts of bronchiolar epithelium showed characteristic features, including positivity for specific human antigens, and extensive regeneration was observed within 8 weeks after implantation. In addition, a few alveolar type II epithelial cells expressing prosurfactant protein C were detected in some areas. The distal alveolar spaces were filled with protein-rich material and were markedly dilated. Abundantly ciliated secretory epithelium, which was similar to normal adult bronchiolar epithelium, was observed within 16 weeks after implantation in the mice. All of the human lung tissue specimens that were implanted subcutaneously into the backs of the mice developed well and remained viable for 20 weeks. Each type of adult human lung epithelial cell showed a different mode of proliferation. Bronchiolar epithelial cells proliferated earlier, with MIB-1 labeling of up to 20% of the cells in the grafts at 8 weeks, while alveolar type II cells proliferated later, with labeling of up to 5% of graft cells at 12 weeks., Conclusion: This model seems to allow adult human lung epithelial regeneration to be investigated in vivo over the long term., (Copyright 2004 S. Karger AG, Basel)

To confirm whether human cancer-induced stromal cells are derived from bone marrow, bone marrow (BM) cells obtained from beta-galactosidase transgenic and recombination activating gene 1 (RAG-1) deficient double-mutant mice (H-2b) were transplanted into sublethally irradiated severe combined immunodeficient (SCID) mice (H-2d). The human pancreatic cancer cell line Capan-1 was subcutaneously xenotransplanted into SCID recipients and stromal formation was analyzed on day 14 and on day 28. Immunohistochemical and immunofluorescence studies revealed that BM-derived endothelial cells (X-gal/CD31 or H-2b/CD31 double-positive cells) and myofibroblasts (X-gal/alpha-smooth muscle actin or H-2b/alpha-smooth muscle actin double-positive cells) were present within and around the cancer nests. On day 14, the frequencies of BM-derived endothelial cells and BM-derived myofibroblasts were 25.3+/-4.4% and 12.7+/-9.6%, respectively. On day 28, the frequency of BM-derived endothelial cells was 26.7+/-9.7%, which was similar to the value on day 14. However, the frequency of BM-derived myofibroblasts was significantly higher (39.8+/-17.1%) on day 28 than on day 14 (P<0.05). The topoisomerase IIalpha-positive ratio was 2.2+/-1.2% for the H-2b-positive myofibroblasts, as opposed to only 0.3+/-0.4% for the H-2b-negative myofibroblasts, significant proliferative activity was observed in the BM-derived myofibroblasts (P<0.05). Our results indicate that BM-derived myofibroblasts become a major component of cancer-induced stromal cells in the later stage of tumor development.

A case of gastric carcinosarcoma with a rare histology is reported. Grossly, a huge ulcerative tumor (Borrmann type 3 tumor, measuring 10 x 6 cm) was observed on the lesser curvature side of the stomach. Microscopically, the tumor consisted of carcinoma and sarcoma components. The main tumor component consisted of an endocrine cell carcinoma exhibiting positive reactions for cytokeratins, chromogranin A, synaptophysin, and CD56. The sarcoma component occupied less than 10% of the entire tumor area and consisted of spindle cells, some of which showed a rhabdomyosarcoma differentiation. Some of the spindle cells also showed an atypical cartilage or osseous differentiation. This sarcoma component exhibited positive staining not only for vimentin and desmin, but also for cytokeratins. Transitions between these two components were occasionally observed. These findings suggest that the sarcoma component in our case most likely originates from the endocrine cell carcinoma component.

Human prostate cancer frequently metastasizes to bone, where it gives rise to osteoblastic bone metastases with an underlying osteoclastic component and subsequent bone pain. However, the importance of osteoclastogenesis in the development of prostate cancer bone lesions in humans is unclear. Osteoprotegerin/osteoclastogenesis inhibitory factor (OCIF) is a member of the tumor necrosis factor receptor family and a novel secreted protein, and it is a negative regulator of osteoclast differentiation, activation, and survival both in vitro and in vivo. In the present study we used a model in which human LNCaP prostate cancer cells that give rise to osteoblastic bone tumors were injected directly into the intramedullary space of human adult bone implanted into nonobese diabetic/severe combined immunodeficient mice to investigate whether the new bone-resorption inhibitor osteoprotegerin/OCIF would inhibit the development of new bone tumors and the progression of established osteoblastic bone tumors. The mice were given consecutive daily s.c. injections of recombinant human OCIF (rhOCIF; 100 micro g/mouse/day) for 2 weeks starting either immediately or 2 weeks after injection of the LNCaP cells. In both protocols, rhOCIF markedly inhibited both the development of bone tumors and the progression of established bone tumor foci quantified by histological examination. Histomorphometrical analysis revealed that rhOCIF markedly reduced the number of osteoclasts and the size of the tumors at the bone sites, but that it had no effect on the local growth of s.c. LNCaP tumors or on LNCaP cell proliferation in culture. These findings demonstrate that osteoclasts play an important role in bone tumor by prostate cancer, and that rhOCIF decreases the LNCaP prostate cancer burden selectively in bone, suppresses the progression of established tumor lesions, and prevents the development of new lesions. These results suggest that inhibition of osteoclastic bone resorption may be an effective therapy for the treatment of prostate cancer that has colonized bone.

The high prevalence of osteoplastic bone metastasis in prostate cancer (PC) is believed to be attributable to the production of osteoblast-stimulating factors by PC cells. Prostate-specific antigen (PSA) is a serine protease and an important serological marker for PC. Exposure of osteoblasts to PSA in vitro was found to result in cell proliferation and marked upregulation of transforming growth factor-beta (TGF-beta) mRNA expression. This PSA-induced increase in osteoblast proliferation was inhibited by anti-TGF-beta antibodies and serine protease inhibitors. In vivo, PSA markedly enhanced osteoplastic changes in human adult bone implanted into NOD/SCID mice without PC cells, and alpha(1)-antichymotrypsin prevented the PSA-induced increase in bone volume. PSA promotes osteoplastic change by activating an osteoblast autonomous mechanism that is independent of the production of bone growth factors by PC cells.

Bone is the most common site of metastasis in prostate cancer (PC), and to generate an animal model to investigate the basis of the unique organ tropism of PC cells for bone, we engrafted humanized non-obese diabetic/severe combined immunodeficient (NOD/SCID-hu) mice with human adult bone (HAB) and lung (HAL). Human PC cell lines LNCaP (1 x 10(7)) and PC-3 (5 x 10(6)) were injected into male NOD/SCID-hu mice via the lateral tail vein at 3-4 weeks after implantation. At 8 weeks after the injection, LNCaP and PC-3 cells had metastasized specifically to HAB in 35 and 65%, respectively, of the mice. The tumors formed by LNCaP appeared to be the osteoblastic type, whereas the PC-3 tumors consisted of osteolytic lesions without any surrounding osteogenic response. A feature of experimental metastasis of PC in NOD/SCID-hu mice was its specificity for HAB tissue. Human PC cells had no or very low metastatic potential in regard to implanted HAL, mouse bone, or native mouse bone. These findings indicate that metastasis of PC cells to HAB is both species and tissue specific. The availability of this small animal model could provide a useful tool for identifying and analyzing important features of the human PC metastatic process that cannot be addressed in conventional metastasis models.

Just like in biological systems, the GAPDH-catalyzed oxidation of aldehyde to carboxylate proceeds in conjunction with 1,4-selective reduction of NAD + to NADH model compounds [Eq. (1)]. The combination of GAPDH- and LDH-type transfer reactions is also described here as a system mimic for the NAD + /NADH redox cycle in anaerobic glycolysis. GAPDH=D-glyceraldehyde-3-phosphate dehydrogenase, LDH=L-lactate dehydrogenase., (© 1998 WILEY-VCH Verlag GmbH, Weinheim, Fed. Rep. of Germany.)

We examined 71 cases of bronchopulmonary dysplasia (BPD) at autopsy and divided them into five groups on the basis of the patients' survival time, studying on the histological changes in the airways for the purpose of clarifying the pathogenesis of BPD from hyaline membrane disease (HMD). Furthermore, bronchiolar occlusion was classified into four types: secretion, obliterative bronchiolitis, intraluminal plug, and hyperplasia of bronchiolar components. The same occlusive findings as in bronchioli and hyaline membrane were observed from respiratory bronchioles to alveolar ducts. However, there was no obvious correlation between airway lesions and accompanying alveolar lesions excepts three cases of obliterative bronchiolitis. Furthermore, immunohistochemical studies with anti-human SOD antibodies were performed. Mn-SOD was positive for alveolar macrophages in longer surviving infants without significant correlation with histological variation, whereas slightly positive or negative in infants who died within 1 week; CuZn-SOD was rarely positive in any cases. These results is highly correlated to the pathogenesis of BPD and to its pathological advancement with its clinical course.

Eccrine adenocarcinoma of the lacrimal sac region is described in a 48-year-old man. The case was first diagnosed as an adenocarcinoma and removed by dacryocystectomy, but unfortunately the neoplasm recurred after a period of 1 year. Examinations with periodic acid-Schiff (PAS) and several antibodies indicate that this is a hitherto undescribed eccrine adenocarcinoma, and finally the case was managed by orbital exenteration. This is the first case of eccrine adenocarcinoma of the lacrimal sac region to be documented in the world literature.

We have studied the expression of glial fibrillary acidic protein(GFAP), an astrocyte specific protein in the normal developing human retina using anti-GFAP antibody. GFAP positive cells were first detected at 24 gestational weeks(GW) in the nerve fiber and ganglion cell layers in the vicinity of the optic disc. Over subsequent weeks, GFAP positive cells covered larger regions of the retina. Some of the processes of these cells terminated in sucker like end-feet upon blood vessels of the nerve fiber layer. A second population of GFAP positive cells existed as perivascular glia in the nerve fiber layer in the early stage of fetal development. In the adult retina perivascular glia were found on vessels throughout the nerve fiber and in the inner portion of the inner plexiform layers. Staining of Müller cells end-feet was obtained only in the adult retina. These results support the views that in the human retina, GFAP positive cells first appear at 24 GW in the region near the optic disc, covering the whole retina at subsequent ages.

The oculocerebrorenal syndrome of Lowe (OCRL), an X-linked disorder involving several organ systems, including the eyes, nervous system, and kidneys, is often difficult to diagnose because few pathologic data of diagnostic features about OCRL are available, and its rarity has hampered comprehensive investigations into its clinical spectrum. Recently, the genetic and biochemical abnormalities responsible for this syndrome have been reported. We have synthesized a cDNA probe of the OCRL locus using a polymerase chain reaction, in which there is no homology of cDNA sequence with human inositol polyphosphate-5-phosphatase (HUMINP5P); we have taken a genetic approach to diagnose this disorder in a 10-year-old male by using Northern blotting and have demonstrated the expression of mRNA in human tissues of a 17-week fetus by in situ hybridization. This paper presents a new method that should be an easy and helpful tool for diagnosing OCRL and that contributes a new aspect of this syndrome through in situ hybridization histochemical staining of normal fetal tissues.

A case of inflammatory pseudotumor of the lacrimal sac is presented. The patient was first consulted for epiphora and swelling of the right lacrimal sac region. A mass was found on computed tomography (CT) and finally it was removed by dacryocystectomy. The diagnosis of inflammatory pseudotumor was confirmed by histopathological sections.

Morphological studies were done on 109 placentae of 6 to 43 gestational weeks. Soft x-ray figures are useful for detecting the development of the placenta, which is closely correlated to enlargement of cotyledon and vascular growth in the chorionic villi. At histological figures, chorionic villi, corresponding to intermediate mature villi at the early gestational weeks, reveal large size with edematous stroma and prominent interstitial cells. Their size becomes smaller with aging, with decreased interstitial cells and stroma. At the early gestational period until 23 weeks, chorionic villi are lined by two cell layers of S-(syncytial) and C-(cytotrophoblastic) cells. After 24 gestational weeks C-inner lining decreases in number. Syncytial knots become marked after 32 weeks. As aging, the intervillous space becomes narrow and is occupied by the small sized terminal and mature chorionic villi with congestive capillaries. Syncytial knots and fibrin deposit around chorionic villi are increased with placental aging. By the immunohistoenzymatical examination, S-lining is positive by hCG (human Chorionic Gonadotropin) at the early gestation, but is markedly positive by hPL(human Placental Lactogen) and SP-1 (Specific Protein 1) lately.