Translating discovery in zebrafish pancreatic development to human pancreatic cancer: biomarkers, targets, pathogenesis, and therapeutics.

Abstract Experimental studies in the zebrafish have greatly facilitated understanding of genetic regulation of the early developmental events in the pancreas. Various approaches using forward and reverse genetics, chemical genetics, and transgenesis in zebrafish have demonstrated generally conserved regulatory roles of mammalian genes and discovered novel genetic pathways in exocrine pancreatic development. Accumulating evidence has supported the use of zebrafish as a model of human malignant diseases, including pancreatic cancer. Studies have shown that the genetic regulators of exocrine pancreatic development in zebrafish can be translated into potential clinical biomarkers and therapeutic targets in human pancreatic adenocarcinoma. Transgenic zebrafish expressing oncogenic K-ras and zebrafish tumor xenograft model have emerged as valuable tools for dissecting the pathogenetic mechanisms of pancreatic cancer and for drug discovery and toxicology. Future analysis of the pancreas in zebrafish will continue to advance understanding of the genetic regulation and biological mechanisms during organogenesis. Results of those studies are expected to provide new insights into how aberrant developmental pathways contribute to formation and growth of pancreatic neoplasia, and hopefully generate valid biomarkers and targets as well as effective and safe therapeutics in pancreatic cancer.

Adenocarcinoma fetal bien diferenciado de pulmón en una mujer de 26 años / Well differentiated fetal adenocarcinoma of the lung in a 26 year old woman

El adenocarcinoma fetal bien diferenciado de pulmón es un tumor raro compuesto por glándulas neoplásicas ricas en glucógeno y túbulos que se parecen al pulmón fetal entre la semana 10 y 16 de gestación[1]. Se presenta el caso de una mujer de 26 años, con antecedentes de bronquitis aguda y tabaquismo, cuyos hallazgos clínicos, imaginológicos, macroscópicos y microscópicos fueron indicativos de esta neoplasia. Se le practicó lobectomía inferior izquierda.

Well differentiated fetal adenocarcinoma is a rare lung tumour that is composed of glycogenrich neoplasic glands and tubules that resemble fetal lung at 10 to 16 weeks of gestation. In this report, we present a case of a 26 year old woman with a history of acute bronchitis and smoking, on which the clinical, imaging, macroscopic and microscopic features were compatible with this neoplasm. Lobectomy was performed of the left lower lobe.

Regulation of human lung adenocarcinoma cell migration and invasion by macrophage migration inhibitory factor.

Macrophage migration inhibitory factor (MIF) is expressed and secreted in response to mitogens and integrin-dependent cell adhesion. Once released, autocrine MIF promotes the activation of RhoA GTPase leading to cell cycle progression in rodent fibroblasts. We now report that small interfering RNA-mediated knockdown of MIF and MIF small molecule antagonism results in a greater than 90% loss of both the migratory and invasive potential of human lung adenocarcinoma cells. Correlating with these phenotypes is a substantial reduction in steady state as well as serum-induced effector binding activity of the Rho GTPase family member, Rac1, in MIF-deficient cells. Conversely, MIF overexpression by adenovirus in human lung adenocarcinoma cells induces a dramatic enhancement of cell migration, and co-expression of a dominant interfering mutant of Rac1 (Rac1(N17)) completely abrogates this effect. Finally, our results indicate that MIF depletion results in defective partitioning of Rac1 to caveolin-containing membrane microdomains, raising the possibility that MIF promotes Rac1 activity and subsequent tumor cell motility through lipid raft stabilization.

Tumors in mice transgenic for the envelope protein of Jaagsiekte sheep retrovirus.

Jaagsiekte sheep retrovirus (JSRV) is the causative agent of ovine pulmonary adenocarcinoma (OPA), a contagious lung cancer in sheep. Previous studies have shown that the JSRV envelope protein (Env) functions as an oncogene, in that it can morphologically transform rodent fibroblast and epithelial cell lines. To obtain a small animal model for JSRV-induced OPA, we generated a transgene expressing an epitope-tagged JSRV Env under control of the lung-specific Surfactant Protein A (SPA) promoter. Transgenic mice containing the SPA-Env-HA transgene showed low efficiency but specific expression in the lung. F1 male progeny from one transgenic founder developed subdermal lipomas that expressed the transgene. These results indicate that the JSRV Env protein is capable of inducing tumors in transgenic mice, and in other cell types besides lung epithelial cells.

Differential expression of integrin mRNAs and proteins during normal rat mammary gland development and in carcinogenesis.

A rat model was used to address the roles of integrins in the regulation of normal mammary epithelial cell (MEC) growth and differentiation and in mammary carcinogenesis. The expression of integrins alpha5, alpha6, beta1, and beta4 was examined via Northern and Western blotting analyses in freshly isolated MEC from various postnatal developmental stages. mRNAs for all four integrins were detectable at puberty and were increased during pregnancy. During lactation, the expression of alpha5, alpha6, and beta1 integrin mRNAs reached a peak, whereas that of beta4 integrin decreased dramatically. At day 7 of involution, the levels of all four integrin mRNAs were similar to or slightly higher than that of the pubertal mammary gland. Although alpha5 integrin protein decreased during pregnancy and lactation, beta1 and beta4 integrin proteins had similar profiles as the expression of their respective mRNAs, suggesting that integrin gene expression is regulated at both transcriptional and post-transcriptional levels. All four integrins were heterogeneously expressed in 7,12-dimethylbenz[a]anthracene- and N-nitroso-N-methyl-urea-induced mammary tumors and in RBA and NMU rat mammary tumor cell lines. Adhesion assays showed that isolated MEC interacted with fibronectin to a greater extent than with laminin and collagen I in vitro, and that tumor cells with altered integrin expression exhibited greater adhesive ability to various substrata. Together, our results indicate that alpha5, alpha6, beta1, and beta4 integrins are differentially expressed during normal MEC development and in mammary tumors, supporting the hypothesis that these integrins play important yet complex roles in the mammary gland.

Primary adenocarcinoma of the vulva, possibly cloacogenic. A report of two cases.

Primary adenocarcinoma of the vulva, arising in continuity with the epidermis and unrelated to the underlying mucus glands, is a distinctly uncommon neoplasm. The origin of such an unusual tumor, although attributed to cloacal remnants, remains speculative. We describe two patients with this rare lesion. No other primary tumor was found in either of the two after a thorough investigation. One patient was treated with radical vulvectomy and was free of disease for 10 years, until her death from unrelated causes. The second patient was treated with wide local excision and was free of disease four years postoperatively. Our experience indicates the need to recognize this tumor as a primary and not metastatic neoplasm of the vulva. We also noticed that in both cases, despite its histologic malignancy and ulceration, the tumor was superficial in its extent and without any tendency for deeper invasion. It can therefore be treated effectively with wide local excision, thus eliminating the need for radical vulvectomy.

[Bladder adenocarcinoma. Report of 2 new cases]. / Adenocarcinoma vesical. Aportación de dos nuevos casos.

Another two cases of bladder adenocarcinoma (ADC), seen in 1988, are described herein. The most important aspects relative to tumor origin--urothelial and embryonal--are discussed. We review its clinical features and diagnosis, not unlike those of transitional cell tumors, although histologically different. We underscore the therapeutic aspects and poor prognosis in most of the cases.

Computed tomography of urachal carcinoma.

Urachal carcinoma arises in the clinically silent extraperitoneal space between the bladder apex and the umbilicus. Computed tomography was used to correctly diagnose and stage urachal cancer in two patients. In one case a mass was localized to the bladder wall and immediate juxtavesical region; in the other case an advanced locally invasive lesion was seen to engulf and fisulize loops of small bowel and extend through the umbilicus. Urachal carcinoma has a highly characteristic appearance and location on CT images.

Adenocarcinoma embrionario infantil testicular: estudio de 10 casos / Infantile testicular embryonal adenocarcinoma: study of 10 cases

Se analizan las historias clínicas de un grupo de pacientes operados por presentar adenocarcinoma embrionario infantil. Se recopilan las láminas histopatológicas de estos pacientes y se realiza un estudio retrospectivo de los mismos para comprobar el diagnóstico de la enfermedad. Se analizan la incidencia, la forma de presentación y se indica el tratamiento llevado a efecto, así como la evolución de estos pacientes

Adenocarcinoma embrionario infantil testicular: estudio de 10 casos / Infantile testicular embryonal adenocarcinoma: study of 10 cases

Se analizan las historias clínicas de un grupo de pacientes operados por presentar adenocarcinoma embrionario infantil. Se recopilan las láminas histopatológicas de estos pacientes y se realiza un estudio retrospectivo de los mismos para comprobar el diagnóstico de la enfermedad. Se analizan la incidencia, la forma de presentación y se indica el tratamiento llevado a efecto, así como la evolución de estos pacientes

Non-clear-cell adenocarcinoma arising in vaginal adenosis.

We report a case of adenocarcinoma of the vagina occurring in a woman without exposure to diethylstilbestrol. The adenocarcinoma arises in benign adenosis and lacks a clear-cell component. Both the adenosis and adenocarcinoma appear to be of müllerian origin.

Benign glandular inclusions in lymph nodes, endosalpingiosis, and salpingitis isthmica nodosa in a young girl with clear cell adenocarcinoma of the cervix.

A 12-year-old girl underwent radical surgery for clear cell adenocarcinoma of the endocervix. Bilaterally dilated fallopian tubes with hyperplastic mucosal folds and salpingitis isthmica nodosa were found in association with benign glandular inclusions in a para-aortic lymph node and in the serosa of pelvic organs. Changes in the müllerian-derived epithelium appear to be a common denominator of these unusual lesions in this young girl. A primary growth disturbance of the cells of the müllerian system, which was conditioned during embryonic development and manifested itself later in life in response to appropriate stimuli associated with menarche, is postulated as the underlying abnormality.

[Adenocarcinoma in bladder exstrophy]. / Adenocarcinoma en extrofia vesical.

We present a case of vesical extrophy complicated by an adenocarcinoma in a 35-year old patient. It is this type of neoformation which most frequently affects the extrophic bladder and which, contrary to what has happened in most of the cases published, quickly presented bone and skin metastases.

Prenatal diethylstilbestrol exposure and human genital tract abnormalities.

The incidence of clear cell adenocarcinoma of the vagina and cervix associated with intrauterine exposure to DES and similar compounds during the first half of pregnancy has increased. Ninety percent of these cancers have occurred in patients 14 years of age or older. Although these carcinomas are exceedingly rare, nonneoplastic abnormalities including vaginal adenosis, cervical eversion (ectropion), and transverse cervical and vaginal ridges are frequent in the exposed population, particularly if the drug was administered early in pregnancy. Current evidence favors a disturbance in development of the müllerian duct as the explanation of these changes. Whether DES is only a teratogen or also a carcinogen is unknown, as is the possible role of other factors in the development of cancer. An increased incidence of cancer among exposed males has not been documented.

Trabecular carcinoma of the skin: an ultrastructural study.

We report the electron microscopic studies of three trabecular carcinomas of the skin. The presence of neurosecretory granules in all three tumors suggests that trabecular carcinoma originates from one of the neurocrest derivatives, most probably, Merkel cells. The ultrastructural findings confirm Toker's original concept that trabecular carcinomas comprise a distinct group of skin tumor. The recognition of these tumors would enable one to make such a diagnosis on frozen section, which, in turn, might provide an opportunity for more specific cytochemical and immunofluorescent characterization.

Clear cell carcinoma of the uterine endocervix with an in situ component.

In the past all clear cell carcinomas of the female genital tract were thought to arise from mesonephric remnants. Recently increasing evidence has related their origin to müllerian rather than mesonephric epithelium. One of the main reasons that has been advanced to support their mesonephric origin has been their occurrence in the uterine cervix and vagina, sites of mesonephric remnants. However, no clear evidence for mesonephric origin of clear cell carcinoma of the cervix and vagina has been ever provided. In contrast, there is substantial evidence that diethylstilbestrol-related clear cell carcinomas of the cervix and vagina are müllerian in origin. We report here a case of an exophytic clear cell carcinoma with an in situ component, involving the endocervical epithelium. The in situ lesion clearly indicates müllerian origin of the tumor, which occurred in the absence of prenatal exposure to diethylstilbestrol. This supports the general agreement that clear cell carcinomas of the cervix are müllerian in origin, whether diethylstilbestrol-related or not.

Clear cell adenocarcinoma of the uterine cervix: a histological and histochemical study.

A case of Mullerian clear cell adenocarcinoma of the uterine cervix occurring in a young women is presented. A detailed histological and histochemical study of this type of tumour is important so as to separate it from the clear cell tumour of mesoenphric origin. The association of Mullerian clear cell adenocarcinoma and other abnormalities of the vagina and cervix with the administration of maternal nonsteroidal oestrogens has been recently stressed in the literature. However, our patient is illustrative of the 30-50% of cases reported to date which have few if any of the associated abnormalities of the genital tract and have no known exposure to non-steroidal oestrogens.