Solitary mast cell tumor of the lung

An extremely rare solitary mast cell tumor of the lung was studied histologically, immunohistochemically, and ultrastructurally. The histologic features of the tumor included nodular growth of well-differentiated mast cells and clear cells with no granules. The current case is the third case of a solitary mast cell tumor (granuloma) of the lung in the literature. Clinicopathologic features of this tumor are compared with the other two cases reported previously in the international literature, and the nature of the clear cells is discussed.     

Modulation of tumor angiogenesis by stem cell factor

Mast cells accumulate within solid tumors and can release many angiogenic factors, suggesting that they may modulate vascularization of tumors. Stem cell factor (SCF) stimulates mast cell migration, proliferation, and degranulation and therefore may influence mast cell behavior within tumors. We investigated the contribution of SCF to tumor angiogenesis by manipulating its level in mammary tumors. Sense or antisense cDNA fragments of rat SCF were ligated into an episomal expression vector. Ethylnitrosourea-induced rat mammary tumor cell lines were transfected with vector containing either control (no insert, C-P), sense (S-P), or antisense (AS-P) SCF DNA. The functional nature of the transfectants was confirmed by measuring SCF in cell lysates and conditioned media. Immunohistochemical analysis of the tumors induced in Berlin-Druckrey rats by these transfected cells demonstrated that mast cell number and microvascular density were significantly higher in S-P tumors and significantly lower in AS-P tumors, compared with C-P tumors. The expression of von Willebrand factor, an endothelial cell marker, showed a similar pattern. AS-P tumors were significantly smaller than either C-P or S-P tumors. These data suggest that SCF modulates tumor growth and angiogenesis via the involvement of mast cells.     

Prolactin binding and localization in rat mammary tumor mast cells

We found that prolactin is taken up by mast cells residing in prolactin-dependent, 7,12-dimethylbenzanthracene-induced rat mammary tumors. Light and electron microscopic immunocytochemistry showed that mast cells concentrate prolactin in their cytoplasmic granules. No prolactin was found on mast cell surface membranes or in their nuclei. In primary cultures of tumor cells, mast cells were found mainly in the periphery of dome structures and these cells concentrated prolactin. When purified rat peritoneal mast cells were incubated with 125I-labeled prolactin, uptake was time, energy, and temperature dependent. Seventy % of accumulated prolactin was released intact from cytoplasmic granules by C48/80-induced degranulation. A mouse mastocytoma cell line also took up and released prolactin. These cells contained prolactin receptors (Kd = 4.5 nM) as determined in whole cells (approximately 3150 sites/cell) and in crude membranes (approximately 180 fmol/mg protein). We conclude that mast cells might significantly influence mammary tumor growth by accumulating and releasing prolactin within tumor tissue.     

Solitary fibrous tumor of the oral mucosa--morphological and immunohistochemical profile in the differential diagnosis with hemangiopericytoma

The objective was to investigate two cases of solitary fibrous tumor (SFT) of oral mucosa, emphasizing the differential diagnosis with one case of oral hemangiopericytoma (HPC), in terms of their morphological and immunohistochemical features. Solitary fibrous tumors showed cellularity and collagenization varying from area to area, focal perivascular hyalinization, scattered giant nuclei cells and abundant mast cells throughout the tumor. The hemangiopericytoma case exhibited thin-walled and dilated vessels lined with flat endothelial cells, identified by "staghorn appearance". Tumoral cells of solitary fibrous tumor exhibited immunohistochemical positivity for CD34, as well as endothelial cells. The hemangiopericytoma was positive only in endothelial cells. In solitary fibrous tumor, alpha-smooth muscle actin, h-caldesmon and laminin stained the wall vessels. In hemangiopericytoma, on the other hand, the wall vessels were positive only for laminin, which staining was also observed in perivascular tumoral cells. The morphological and immunohistochemical differences observed allowed us to infer these lesions constitute distinct entities.     

Mast cell kinetics during tumor growth

The behavior of mast cells was studied during tumor growth. Sarcoma 13, and normal syngeneic kidney, as control, were implanted subcutaneously in BALBc mice. The number of mast cells in the hypodermis and peritumoral tissue increased 3-fold, 20 days after implantation. In the peritumoral tissue, mast cell degranulation increased together with tumor growth, while in the dermis and hypodermis, it first decreased and only became evident on day 20. Mitosis and mast cell degranulation, more conspicuous in tissues near the tumor, seem to indicate the existence of tumoral factors which spread slowly from the tumor to distant zones. The role of mast cells in peritumoral tissues will be evaluated in the near future.     

Immunoreactive vasoactive intestinal polypeptide in acinic cell carcinoma of the parotid gland

Vasoactive intestinal polypeptide (VIP) in the neoplastic cells of acinic cell carcinomas arising in the human parotid gland was found immunohistochemically, whereas other parotid gland tumors, such as pleomorphic adenoma, Warthin's tumor, oxyphilic adenoma, mucoepidermoid carcinoma, adenocarcinoma, and adenoid cystic carcinoma, did not show positive immunoreactivity for VIP. The acinic cell carcinoma stained with Grimelius impregnation and had dense core granules immunoreactive with anti-VIP serum. Moreover, a comparatively high concentration of immunoreactive VIP was detected by radioimmunoassay in an acinic cell carcinoma, whereas VIP concentration of the other tumors was undetectable.     

Papillary and cystic tumor of the pancreas. Two cases indistinguishable from islet cell tumor

Two cases of large cystic tumor of the pancreas in two young women are reported. Gross features and conventional light microscopic appearances of these tumors were consistent with those described as being the so-called papillary and cystic tumor (PCT) or solid and cystic tumor. Immunohistochemical staining for neuron-specific enolase was positive diffusely in both cases. Special stainings with Grimelius' silver impregnation, and stainings for insulin, glucagon, and somatostatin also were positive, although the population of positive cells was different in each case. Ultrastructural examinations confirmed the presence of numerous granules, probably neurosecretory, within the cytoplasm of many tumor cells in each case. Therefore, current cases were indistinguishable pathologically from the cystic nonfunctioning islet cell tumor. This study suggests that some PCT of the pancreas consist of endocrine cells predominantly.     

Conditional ROCK activation in vivo induces tumor cell dissemination and angiogenesis

Progression of tumors to invasive and metastatic forms requires that tumor cells undergo dramatic morphologic changes, a process regulated by Rho GTPases. Elevated expression of RhoA and RhoC, as well as the Rho effector proteins ROCK I and ROCK II, are commonly observed in human cancers and are often associated with more invasive and metastatic phenotypes. To examine how ROCK contributes to the progression of solid tumors, we established a conditionally activated form of ROCK II by fusing the kinase domain to the estrogen receptor hormone-binding domain (ROCK:ER). ROCK:ER-expressing colon carcinoma cells grown as tumors in immunocompromised nude mice organized into discrete clusters surrounding blood vessels. However, ROCK:ER activation resulted in the aggressive dissemination of tumor cells into the surrounding stroma, indicating that increased ROCK signaling is sufficient to promote invasion from solid tumors. In addition, tumors in which ROCK:ER was activated were more highly vascularized, indicating that ROCK contributes to tumor angiogenesis. ROCK:ER activation resulted in changes to epithelial morphology and organization that facilitated motility in vitro, likely by inducing the redistribution of proteins such as ezrin, as well as adherens junction and extracellular matrix-binding proteins. These results suggest that ROCK inhibitors would be useful antimetastatic and antiangiogenic chemotherapeutic agents in tumors associated with elevated RhoA, RhoC, ROCK I, or ROCK II expression.     

Three isoforms of annexin I are preferentially expressed in normal esophageal epithelia but down-regulated in esophageal squamous cell carcinomas

The development and progression of human cancer are believed to be due to the alterations of multiple genes or/and their protein products. For identifying the proteins associated with esophageal cancer, we analysed the protein profiles of 24 pairs of esophageal squamous cell carcinomas/matched adjacent normal epithelia. Microdissection of routinely unstained frozen sections was performed to purify cancerous and epithelial cells. The protein expression profiles were obtained by two-dimensional electrophoresis. Selected proteins dysregulated in tumors were identified by MALDI-TOF-MS. Three isoforms of annexin I were detected in normal esophageal mucosa and down-regulated in esophageal squamous cell carcinomas. RT-PCR analysis showed annexin I mRNA levels were significantly reduced in 17 out of 24 carcinomas. Immunohistochemistry demonstrated that annexin I appeared strong positive in all normal epithelia layers except basal cells. In cancer tissues, decreased expression of annexin I was observed in 12 out of 16 well differentiated tumors, 16 out of 17 moderately differentiated tumors, and 3 out of 3 poorly differentiated tumors as compared with the corresponding normal esophageal epithelia. There was a significant correlation between annexin I expression and the status of tumor differentiation. Well differentiated tumors presented stronger immunohistochemical reaction than moderately and poorly differentiated tumors. These data suggested that there existed three different isoforms of annexin I in normal esophageal epithelia, which may be the results of post-translational modification. Down-expression of three annexin I isoforms was a frequent event in esophageal carcinogenesis.     

Mast cell: insight into remodeling a tumor microenvironment

Mast cells are of paramount importance to allergies, pathogen immune responses during infections, and angiogenesis, as well as innate and adaptive immune regulations. Beyond all these roles, mast cells are now more and more being recognized as modulators of tumor microenvironment. Notwithstanding mounting evidences of mast cell accumulation in tumors, their exact role in tumor microenvironment is still incompletely understood. In this review, we discuss the significant role of mast cells in the remodeling of tumor microenvironment by either releasing various factors after activation or interacting with other cells within tumor and, as a result, the possible role of mast cell in cancer invasion and metastasis. We also discuss recent findings that mast cells actively release microparticles, which account for the transfer of membrane-type receptor signal and regulatory molecules such as microRNAs to tumor cells and immune cells. These findings on mast cells provide further insights into the complexity of tumor microenvironment remodeling.     

Concurrent hypermethylation of multiple regulatory genes in chewing tobacco associated oral squamous cell carcinomas and adjacent normal tissues

The methylation pattern in the promoter region of p16, DAPK, MGMT and GSTP1 genes was investigated in oral cancer tissues and tumor associated adjacent tissues, using methylation specific PCR assay. The samples constituted 60 primary oral tumors and corresponding adjacent clinically and histopathologically normal mucosa, and buccal epithelial scrapings from 20 normal healthy individuals without any tobacco habits. The incidence of hypermethylation in oral tumor and adjacent mucosa for p16 gene was 66.7 and 50%, for DAPK was 68.3 and 60%, and MGMT gene was 51.7 and 26.7%, respectively. The overall hypermethylation in the three genes in the primary tumor was 86.7%, and corresponding adjacent normal mucosa tissues 76.7%. Hypermethylation was not observed in the promoter region of GSTP1 gene in either the primary tumors or the corresponding adjacent normal mucosa. Absence of aberrant methylation in the four genes was noted in buccal scrapings from normal healthy individuals with no tobacco habits. Thus, a high frequency of promoter region hypermethylation was observed in p16, DAPK and MGMT genes in oral cancer tissues as well as in corresponding adjacent normal mucosa. Our results indicate that epigenetic alteration of these genes is a frequent event in oral cancer, and is an early event observed in normal oral mucosa of the patients, indicating the critical importance of the epigenetic alteration in chewing tobacco associated oral carcinogenesis.     

Basal cell adenoma of the parotid gland. Case report with ultrastructural observations.

A case of basal cell adenoma of the parotid gland is reported. The tumor was studied by electron microscopy, and fine structural features included numerous desmosomes, large secretory granules, and replication of the basal lamina. Myoepithelial cells were not observed. The observations support the view that the tumor is monomorphic and that it arises from serous cells of the acini or intercalated ducts. The tumor may be the benign homolog of the adenoid cystic carcinoma.     

Mast cells in the estrogen-induced transplantable renal tumor of the hamster

Mast cells are frequently seen in and around a variety of malignant tumors. However, mast cells have not been seen in the transplantable estrogen-induced renal tumor of the hamster. In this study the subcutaneously transplanted renal tumor of Kirkman was examined using a variety of fixation techniques. All tissues were stained in toluidine blue (0.5% solution at a pK of 3.8). Mast cells were seen in great numbers only in tumor tissue frozen in isopentane cooled with liquid nitrogen at −155 C and cut on a cryostat at −20C. This would indicate the importance of the method of preparation of such fastidious cells. The hamster tumor provides, then, an excellent source of mast cells for study in a tumor environment.     

Different expression levels of lumican in human carcinoid tumor and neuroendocrine cell carcinoma

Lumican is a member of the small leucine-rich proteoglycan (SLRP) family and participates in the maintenance of tissue structures and tumor growth. Neuroendocrine cell tumors (NETs) including carcinoid tumors and NE cell carcinomas (NECs) possess numerous neuroendocrine (NE) granules, and differences between these tumors are in terms of their biological and metastatic aggressiveness during tumor progression. The purpose of this study was to examine the expression of lumican in NETs, and to determine whether the presence of lumican may be associated with the growth of NETs by comparing its expression between carcinoid tumors and NECs. Immunohistochemically, the positivity rates of lumican expression in the cytoplasm of the tumor cells were 87.5% in carcinoid tumors and 37.5% in NECs. Those of lumican expression in the stroma adjacent to the tumors were 90.1% in carcinoid tumors and 79.2% in NECs. In situ hybridization analysis revealed the lumican mRNA expression in the cytoplasm of carcinoid tumor and NEC cells. Ultrastructurally, the lumican protein was observed in the rough endoplasmic reticulum and NE granules of NETs and interspaces of collagen fibers. Furthermore, RT-PCR analysis revealed the presence of lumican mRNA in NEC cell lines. These results indicate that the higher expression level of cytoplasmic lumican in carcinoid tumors than in NECs may play a role in the slow growth of these tumors.     

Acceleration of tumor growth and peri-tumoral blood clotting by imatinib mesylate (Gleevec)

Imatinib mesylate (Gleevec) inhibits the BCR-ABL tyrosine kinase in chronic granulocytic leukemia. Previous studies have demonstrated that imatinib mesylate also inhibits the survival and functions of normal mast cells by interfering with the receptor tyrosine kinase for stem cell factor (SCF), c-kit, which is expressed by mast cells. Because mast cells extensively surround many types of cancer and contain powerful anticoagulants such as heparin, we investigated the effects of imatinib mesylate on blood clotting and tumor growth within subcutaneous implants of a mammary adenocarcinoma cell line (4T1) in BALB/c mice. After 5 days of oral treatment with 10 mg/kg of the drug, the average mass of the tumors in treated mice (198 +/- 42 mg, n = 5) was significantly (p < 0.05) greater than the average mass of the tumors from untreated (control) mice (60 +/- 23 mg, n = 5). Moreover, the tumors in the treated mice were frequently surrounded by large lakes of clotted blood that were not evident in tumors from the control mice. Accelerated growth and blood clotting were also observed in tumor-bearing mice treated with heparinase I enzyme to destroy endogenous mast cell heparin and in NDST-2 knockout mice in which there is a targeted disruption in the gene coding for mast cell heparin synthesis. We conclude that imatinib mesylate accelerated the growth and peri-tumoral blood clotting of implants of mammary adenocarcinoma in mice. These results suggest that imatinib mesylate may have significant effects on mast cells infiltrating tumors, in addition to its other biologic activities. Our results also indicate that the mechanism of this effect may be related to the anticoagulant properties of mast cell heparin.     

Collagenolytic mechanisms in tumor cell invasion

Summary Connective tissue stroma and basement membrane structures probably present natural barriers to the migration of tumor cells. It has therefore been proposed that collagenolytic enzymes are required to facilitate the spread and invasion of tumor cells into host tissues. The collagenases and cathepsin B-like enzymes are thought to be involved, but the cellular source of collagenolytic activity at the tumor: host interface or invasion zone' remains obscure in most cases. The invasion zone of different tumors is very variable with regard to the type and numbers of host or tumor cells, as well as the type of collagenous matrix, and few generalities can be made. The existence within a tumor of specialised subpopulations of cells which have different metastatic potential has been postulated. As a consequence it seems plausible that the phenotypic expression of highly invasive or metastatic tumor cells should include the potential for generating collagenolytic activity. Immunolocalisation studies have demonstrated the production of type I and type IV collagenases at sites of tumor invasion, but it does not appear to be a continuous process and only a small proportion of tumor and/or host cells elaborate enzyme at any one moment. Collagenase production is invariably microenvironmental in nature and it seems likely that local host:tumor cell interactions are important in modulating collagenolysis. Macrophages and mast cells have been shown to stimulate collagenase expression by tumor and stromal cells in vitro, and it is proposed that these cells may assume a contributory role for the induction of collagenolytic activity in vivo. The collagenolytic mechanisms that operate at micro-foci of host:tumor junctions probably depend upon the type of collagen, the cellular composition and the extracellular ionic conditions of each invasion site. Either tumor or host cells may elaborate enzymes, this being dependent upon the type and/or tissue location of the invasive tumor.     

Density of mast cells and microvessels in minor salivary gland tumors

The aim of this study was to investigate the density of mast cells and microvessels in minor salivary gland tumors. Forty-one cases of minor salivary gland tumors (pleomorphic adenoma, n?=?10; adenoid cystic carcinoma, n?=?11; mucoepidermoid carcinoma, n?=?10; and polymorphous low-grade adenocarcinoma) were investigated using immunohistochemistry for mast cell tryptase and von-Willebrand factor. Density of mast cells was higher in mucoepidermoid carcinoma; however, no differences in the number of these cells were observed between the different types of tumors (p?>?0.05). The number of mast cells was higher in periparenchymal areas in all tumors, but the difference was not significant (p?>?0.05). Mucoepidermoid carcinoma showed the largest number of periparenchymal mast cells, whereas pleomorphic adenomas showed the smallest number of intraparenchymal mast cells (p?>?0.05). The highest microvessel density was observed in mucoepidermoid carcinomas, being this difference statistically significant when mucoepidermoid carcinoma was compared to pleomorphic adenoma (p?=?0.0034) and polymorphous low-grade adenocarcinoma (p?=?0.004). Microvessel density was significantly higher in adenoid cystic carcinoma when compared to pleomorphic adenoma (p?=?0.0406) and polymorphous low-grade adenocarcinoma (p?=?0.0123). Comparison of mast cells and microvessel densities showed no significant difference between tumors. A quantitative difference in mast cells and microvessels was observed, particularly in mucoepidermoid carcinoma, a finding supporting the aggressive behavior of malignant salivary gland tumors without myoepithelial differentiation. Further studies are needed to determine the role of mast cells in angiogenesis, as well as in the development and biological behavior of these tumors.     

MRP和P—gp与食管鳞癌发生发展的关系研究

目的探讨MRP、P-gP在食管鳞癌中的表达情况及与食管鳞癌发生发展的关系。方法采用免疫组织化学sP法研究了49例食管鳞癌组织中MRP和P-gp的表达情况,探讨二者与肿瘤发生发展的关系。结果49例食管鳞癌癌组织、癌旁非典型增生组织、正常食管黏膜组织MRP阳性表达率分别为63．3％（31／49）、40．0％（12／30）和20．4％（10／49）。癌组织中MRP阳性表达率与相应的癌旁组织、正常食管黏膜组织比较,差异有显著性（P〈0．05）。49例食管鳞癌癌组织、癌旁非典型增生组织、正常食管黏膜组织中P-gP阳性表达率分别为61．2％（30／49）、36．7％（11／30）和18．4％（9／49）。癌组织中P-gp阳性表达率与相应的癌旁组织、正常食管黏膜组织比较,差异有显著性（P〈0．05）。结论食管鳞癌组织、癌旁不典型增生组织及正常黏膜组织中MRP和P—gP阳性表达率均依次降低,并且癌组织与癌旁不典型增生组织和正常黏膜组织中MRP和P—gP阳性表达间相比,差异有显著性,表明MRP和P-gP参与食管鳞癌的发生发展过程,可作为食管上皮细胞恶性转化的标志。     

Immunohistochemical and biochemical study of a cathepsin B-like proteinase in human colonic cancers

An immunohistological study was carried out on 51 human colorectal adenocarcinomas and eight samples of histologically normal colonic mucosa removed far from tumors, using anti-rabbit cathepsin B and anti-human cathepsin B immunoglobulins. Positive reactions were obtained on tumor cells and macrophage-like cells. However, as these immunoglobulins could not discriminate between cathepsin B and cathepsin B-like proteinases, and as they cross-reacted with cathepsins H and L, a partial characterization of the proteinase activities was performed in order to identify the type of enzyme present in the positive cells. The levels of cathepsins H and L were very low in extracts of colorectal tumors and normal colonic mucosa. A peculiar cathepsin B-like proteinase activity with pH optimum at 6.8 was found in tumor extracts together with the lysosomal cathepsin B, whereas normal colonic mucosa showed only cathepsin B activity (pH optimum, 6.0). These results indicate that lysosomal cathepsin B is responsible for staining of macrophage-like cells found in the lamina propria of colonic mucosa and in the peritumoral stroma. Immunohistochemical staining of colonic tumor cells observed in 29/51 cases seems on the other hand to be primarily due to a cathepsin B-like proteinase. Three colonic tumor cell lines, Colo-205, HT-29, and SW-1116, were also studied using the same methods. These cells produced a latent cathepsin B-like proteinase which, after activation, was similar to that found in tumor extracts. This latent proteinase was detected mainly in the culture media. The cultured colonic tumor cells, after staining by anti-cathepsin B antibodies, showed strongly positive granules. In conclusion, this work demonstrates that malignant colonic cells are the source of a cathepsin B-like proteinase, with optimal activity near neutrality. Its secretion into the extracellular space indicates furthermore, that it may be an important component of the "proteinase cascade" associated with tumor invasion and metastasis.