Relationship between in utero development of the mouse liver and tumor development following transplacental exposure to ethylnitrosourea

Pregnant C3HeB/FeJ mice were treated with ethylnitrosourea (ENU) on one of gestation Days 10, 13, or 15 to determine if ENU treatment at different stages of gestation would result in morphological or quantitative differences in liver tumors induced in the offspring. Liver tumors were counted and measured 6 mo after treatment with ENU. Foci of cellular alteration were identified histologically and counted. Liver tumor number and foci of cellular alteration increased as a function of increasing dose and age at the time of ENU treatment. An inverse relationship between age at the time of treatment and the size of liver tumors was found. The mean tumor volume of male mice exposed on Day 10 of gestation was 123-fold larger than for spontaneous tumors observed in controls. The differences between mean liver tumor volume in mice which had been exposed to ENU on Days 10, 13, or 15 of gestation appeared to be associated with the exponential growth of the fetus during this period of gestation. Unique, large, multinodular foci of cellular alteration were found in mice treated on Day 10 of gestation. The relationship between the stage of gestation and the size of chemically induced liver tumors in these mice is similar to previous observations with transplacentally induced lung tumors in C3HeB/FeJ mice. This indicates that developmentally regulated cell proliferation occurring at the time of carcinogen exposure may affect the subsequent extent of tumor development in both the liver and lung. Therefore, cells transformed during early development may result in tumors that pose a greater biological hazard than those transformed in later development.     

雌激素受体基因多态性与女性雌激素相关肿瘤发病风险的关系

  雌激素受体（ER）存在两种亚型雌激素受体α（ERα）与雌激素受体β（ERβ），是一种能与雌激素（E）特异性结合的糖蛋白，广泛分布于体内多个器官与组织中，其中女性生殖系统与乳腺被认为是E作用的经典靶组织。研究发现，ER基因多态性与女性生殖系统肿瘤及乳腺癌的发生有关。文章从ER的分子结构、功能、作用方式、基因多态性以及与女性生殖系统肿瘤及乳腺癌的关系进行综述。     

Hyperinsulinemia enhances c-Myc-mediated mammary tumor development and advances metastatic progression to the lung in a mouse model of type 2 diabetes

Introduction  

Hyperinsulinemia, which is common in early type 2 diabetes (T2D) as a result of the chronically insulin-resistant state, has now been identified as a specific factor which can worsen breast cancer prognosis. In breast cancer, a high rate of mortality persists due to the emergence of pulmonary metastases.     

So-called "minute pulmonary chemodectoma": a tumor not related to paragangliomas.

Twenty-six cases of so-called "minute pulmonary chemodectoma" are presented. The patient population showed a marked female preponderance, and there appeared to be an association of the lesion with pulmonary injury from a variety of causes including cardiac failure, chronic bronchitis and emphysema, and thromboemboli. Half the cases had multiple tumors. Microscopically, the tumors consisted of nests of cells in the interstitial tissue near small veins. Argentaffin and argyrophil stains failed to demonstrate cytoplasmic granules in any case. By electron microscopy, the nests were composed of large cells with broadly interdigitating processes connected by many well-formed desmosomes. The cytoplasm was filled with numerous 60-A filaments. The Golgi apparatus was prominent, while other organelles were sparse. No secretory granules were identified. It is concluded that the fine structure and lack of silver-positive granules are inconsistent with the morphology of previously reported paragangliomas, but that there is a resemblance at the light and electron microscopic level to meningeal arachnoed cells and the cells of meningiomas.     

A case of huge colon carcinoma and right renal angiomyolipoma accompanied by proximal deep venous thrombosis, pulmonary embolism and tumor thrombus in the renal vein

A preoperative inferior vena cava (IVC) filter is reported to be effective in surgical cases with proximal deep venous thrombosis (DVT) or in which pulmonary embolism (PE) has already developed, and considered to be at high risk of developing secondary fatal PE during or after surgery. However, guidelines for using an IVC filter have yet to be established. The patient in the present report had two huge tumors, ascending colon cancer and renal angiomyolipoma, which occupied the entire right half of the abdomen, coexisting PE, DVT and tumor thrombus in the right renal vein. Secondary PE is fatal in the perioperative period, therefore, the vena cava filters were preoperatively inserted into the supra- and the infrarenal IVC. We successfully removed the tumors without complications. The patient is alive without tumor recurrence and PE or recurrent DVT 1 year and 6 months after surgery. The coexistence of two huge abdominal tumors as potential causes of PE and DVT is extremely rare, and we could have safely undergone the operation, using two vena cava filters in the supra- and infrarenal IVC.     

Post-chemotherapeutic administration of interleukin-12 retards tumor growth and enhances immune cell function: combination therapy using paclitaxel and IL-12

The antineoplastic agent paclitaxel (TAXOL) is a potent inhibitor of tumor cell division that also suppresses lymphocyte proliferative responses. Because chemotherapy-induced immunosuppression may limit the patient's antitumor responses, we investigated the possibility that the T cell stimulatory cytokine interleukin-12 (IL-12) could be used to reverse paclitaxel-mediated lymphocyte suppression. Recognizing that IL-12 treatment following paclitaxel exposure promotes T cell responses in vitro, we evaluated the antitumor efficacy of IL-12 administration concurrent and subsequent to paclitaxel treatment. Simultaneous administration of IL-12 and paclitaxel failed to limit tumor outgrowth or extend survival beyond chemotherapy alone, although IL-12 did not manifest negative effects. In contrast, post-chemotherapeutic IL-12 significantly delayed tumor outgrowth and extended survival in tumor-burdened BALB/c mice. Correlative enhancements in ex vivo immune cell effector function were also observed following paclitaxel and temporally delayed IL-12 therapy. Collectively, these data demonstrate an immunotherapeutic efficacy of IL-12 that augments the chemotherapeutic activities of paclitaxel when delivered in the appropriate temporal sequence.     

Cytologic analysis of renal angiomyolipoma: a comparison of radiologically classic and challenging cases.

BACKGROUND: Angiomyolipoma is a benign kidney tumor with distinctive pathologic and clinical features. Because the prognosis differs from many other renal and retroperitoneal tumors, accurate diagnosis on cytologic material may be important for appropriate management. METHODS: A retrospective analysis of cytologic material from eight patients with histologically confirmed angiomyolipomas was performed. The findings are described. RESULTS: Three cases were diagnosed radiologically as angiomyolipoma, three were diagnosed as renal cell carcinoma, one was diagnosed as a "renal mass," and one was diagnosed as a fat-containing adrenal tumor. Compared with the tumors that were suggestive radiologically of angiomyolipoma, tumors that were suspicious radiologically for renal cell carcinoma tended to contain less fat on cytologic examination. One fat-containing tumor was not diagnosed as angiomyolipoma because the tumor was believed to be adrenal in origin. Cytologically, cohesive stromal fragments were comprised of cells ranging from epithelioid to elongate. Stromal atypia was present in 7 of 8 cases (88%) but was marked in only 2 cases (25%). Thick-walled vessels were noted in 3 of 8 cases (38%). CONCLUSIONS: The cytologic diagnosis of angiomyolipoma is difficult in cases in which the radiologic diagnosis is not clear. The liberal use of immunostains is advised in the evaluation of stromal renal tumors.     

Effect of troglitazone on tumor growth and pulmonary metastasis development of the mouse osteosarcoma cell line LM8

Background  

Osteosarcoma often develops micrometastases in the lung prior to diagnosis, causing a fatal outcome. Therefore, the prevention of pulmonary metastases is critical for the improvement of the prognosis of patients with osteosarcoma. The purpose of this study was to investigate whether troglitazone (TGZ) is considered as possible therapeutics in the treatment of growth and metastasis of osteosarcoma.     

Characterization of a new virus from Mus cervicolor immunologically related to the mouse mammary tumor virus.

A virus, similar to the murine mammary tumor viruses (MuMTV) of the laboratory mouse Mus musculus, was identified in the milk of M. cervicolor popaeus mice. The virus was morphologically indistinguishable from the type-B MuMTV and was thus termed MC-MTV. Radioimmunoassays for the 52,000-dalton major envelope glycoprotein and the 28,000-dalton major internal protein of MuMTV demonstrated that MC-MTV shared some antigenic determinants with both of these MuMTV proteins. This reactivity was clearly different, however, from that observed with all MuMTV tested from M. musculus. MC-MTV had a density of 1.16 g/ml in sucrose and a virion-associated DNA polymerase with a divalent cation preference for Mg2+ over Mn2+. Radioimmunoassays clearly differentiated MC-MTV from the other viruses previously identified from M. cervicolor, i.e., M432, CERV-CI, and CERV-CII. These studies thus identified the first virus from another species that is immunologically related to the MuMTV of M. musculus. Particles similar to MC-MTV were also observed in a spontaneous M. cervicolor popaeus mammary tumor.     

Particular cytochrome P-450-dependent steroid metabolism: a new class of mouse liver tumor markers

An altered pattern of cytochrome P-450-dependent microsomal steroid metabolism was identified in female mouse liver tumors induced by 5,9-dimethyldibenzo[c,g]carbazole, a potent organo-specific liver carcinogen. These tumor tissues were compared to extratumoral liver parenchyme, to normal, fetal and neonatal livers and to spontaneous liver tumors, the frequency of which is very low in the highly hybridized mouse strain (XVIInc/Z) used for liver tumorigenesis. Cytochrome P-450-dependent steroid hydroxylase activities were measured by the identification and quantification of four monohydroxyprogesterone and eight monohydroxytestosterone metabolites. In contrast to a general decrease (50%) of total P-450 in tumor microsomes, the individual steroid hydroxylases were regulated differently. Progesterone 16 alpha- and testosterone 6 alpha-, 6 beta-, 7 alpha- and 16 alpha-hydroxylase activities were decreased 50%, and more, whereas progesterone and testosterone 15 alpha-hydroxylase activities were raised 3-4 times with regard to microsomal protein content and 6-7 times with regard to total P-450. Consequently the most prominent feature of the steroid metabolism by tumor-borne microsomes is the hydroxylation at the 15 alpha-position. Furthermore, minor testosterone 2- and 15 beta-hydroxylase activities showed equally an increase of approximately 4 times (8 times with regard to total P-450). The observed new tumoral pattern of P-450-dependent microsomal steroid metabolism appearing characteristically in spontaneous and chemically induced liver tumors indicates that particular P-450 enzymes are strongly expressed in mouse liver tumors. These enzymes may be used as markers for early stages in liver tumorigenesis.     

Issues and barriers to development of clinically useful tumor markers: a development pathway proposal

There are few tumor markers that are clinically useful in predicting therapeutic responses or patient outcomes despite nearly 20 years of advances in molecular biology. We discuss a variety of issues and barriers that have affected movement of clinical tests from research into clinical practice. Studies of new markers frequently lack clear hypotheses and are generally underpowered to reach statistically valid conclusions. Relevant clinical endpoints may not be possible to evaluate, often leading to suboptimal study designs. Major stumbling blocks exist because studies are rarely comparable. This makes it difficult to determine why results vary from study to study. It also prevents pooling of small datasets for analysis. We propose a tumor marker development pathway that we think will be more efficient and effective. The pathway depends on developing statistically valid study designs, focusing on assay refinement and standardization early in the process, including assay details in publications, and providing data in a format that allows comparison with other studies. The process described should be applicable to development of new technologies that include analysis and interpretation of large, complex datasets. The proposed marker development pathway will require thoughtful refinement and expansion, but it should begin a productive dialog.     

Giant exophytic renal angiomyolipoma masquerading as a retroperitoneal liposarcoma: A case report and review of literature

A 42-years-old lady, presented with a large retroperitoneal mass which was preoperatively diagnosed as a retroperitoneal liposarcoma following an image guided core biopsy. She underwent a margin-negative resection of the retroperitoneal mass (multi visceral resection - enbloc excision of the retroperitoneal mass with a left nephrectomy and a segmental descending colectomy). The final histopathological examination of the resected specimen confirmed an exophytic renal angiomyolipoma (AML) which was extending into the retroperitoneum. AML is a rare benign tumor arising most commonly from the kidney. It can sometimes present as a diagnostic challenge as it mimics a retroperitoneal liposarcoma or a fat-containing renal cell carcinomas closely. We present this case to share our experience of managing a case of giant exophytic AML which resembled retroperitoneal liposarcoma closely and resulted into an aggressive surgery.     

Identification and characterization of CRG-L2, a new marker for liver tumor development

Liver cancer is very common worldwide and the rates of hepatocellular carcinoma (HCC) have increased by over 70% in the last 2 decades in the US. Late diagnosis, because of the lack of clinical symptoms, and decreased hepatic function, because of underlying hepatic disease, lead to the extremely high mortality rates associated with HCC. Clearly, the identification of markers that are expressed early in the development of HCC and that are easily detected in high-risk patients would aid in early diagnosis and increased survival. We present the cloning and characterization of a novel gene, CRG-L2 (Cancer related gene-Liver 2), which displays high expression in murine and human hepatocellular carcinomas. Using in situ hybridization, we show that CRG-L2 mRNA levels are increased early during the development of liver tumors in C3H/HeJ mice, and that in normal tissues CRG-L2 mRNA is restricted to the murine testis and human placenta. Its restricted expression in normal tissues and unique early upregulation during tumor development make CRG-L2 an excellent candidate as a new clinical marker of HCC.     

Development of a circulating miRNA assay to monitor tumor burden: From mouse to man

Circulating miRNA stability suggests potential utility of miRNA based biomarkers to monitor tumor burden and/or progression, particularly in cancer types where serial biopsy is impractical. Assessment of miRNA specificity and sensitivity is challenging within the clinical setting. To address this, circulating miRNAs were examined in mice bearing human SCLC tumor xenografts and SCLC patient derived circulating tumor cell explant models (CDX). We identified 49 miRNAs using human TaqMan Low Density Arrays readily detectable in 10 μl tail vein plasma from mice carrying H526 SCLC xenografts that were low or undetectable in non‐tumor bearing controls. Circulating miR‐95 measured serially in mice bearing CDX was detected with tumor volumes as low as 10 mm3 and faithfully reported subsequent tumor growth.Having established assay sensitivity in mouse models, we identified 26 miRNAs that were elevated in a stage dependent manner in a pilot study of plasma from SCLC patients (n = 16) compared to healthy controls (n = 11) that were also elevated in the mouse models. We selected a smaller panel of 10 previously reported miRNAs (miRs 95, 141, 200a, 200b, 200c, 210, 335#, 375, 429) that were consistently elevated in SCLC, some of which are reported to be elevated in other cancer types. Using a multiplex qPCR assay, elevated levels of miRNAs across the panel were also observed in a further 66 patients with non‐small cell lung, colorectal or pancreatic cancers. The utility of this circulating miRNA panel as an early warning of tumor progression across several tumor types merits further evaluation in larger studies.