The highly aggressive character of melanoma makes it an excellent model for probing the mechanisms underlying metastasis, which remains one of the most difficult challenges in treating cancer. We find that miR-182, member of a miRNA cluster in a chromosomal locus (7q31-34) frequently amplified in melanoma, is commonly upregulated in human melanoma cell lines and tissue samples; this up-regulation correlates with gene copy number in a subset of melanoma cell lines. Moreover, miR-182 ectopic expression stimulates migration of melanoma cells in vitro and their metastatic potential in vivo, whereas miR-182 down-regulation impedes invasion and triggers apoptosis. We further show that miR-182 over-expression promotes migration and survival by directly repressing microphthalmiaassociated transcription factor-M and FOXO3, whereas enhanced expression of either microphthalmia-associated transcription factor-M or FOXO3 blocks miR-182's proinvasive effects. In human tissues, expression of miR-182 increases with progression from primary to metastatic melanoma and inversely correlates with FOXO3 and microphthalmia-associated transcription factor levels. Our data provide a mechanism for invasion and survival in melanoma that could prove applicable to metastasis of other cancers and suggest that miRNA silencing may be a worthwhile therapeutic strategy.microRNA ͉ cancer ͉ invasion M etastasis is a central problem in cancer, yet the mechanisms underlying a cell's ability to extravasate from the primary tumor, circulate, and invade new tissue remain poorly understood. We reasoned that melanoma, one of the most notoriously invasive neoplasia, would provide an excellent model for investigating the alterations that contribute to metastasis. Melanomas are characterized by certain well-defined genetic alterations (reviewed in ref. 1) as well as frequent chromosomal aberrations associated with tumor progression (2). Recent work has also shown that melanomas display genomic alterations involving numerous microRNA genes (3). MicroRNAs (miRNAs) are endogenous noncoding small RNAs that interfere with the translation of coding messenger RNAs (mRNAs) in a sequence-specific manner (4), often to regulate processes involved in development or tissue homeostasis (5-7). Intriguingly, dysregulation of miRNAs has been found to contribute to neoplasia (8). We decided to investigate the possible contributions of miRNA dysregulation to melanoma extravasation, migration, and invasion.We compared the expression of miRNAs in a large cohort of melanoma cell lines with that of normal melanocytes. We found that miR-182, flanked by the c-MET and BRAF oncogenes in the 7q31-34 region that is frequently amplified in melanoma (9, 10), is highly expressed in metastatic melanoma cell lines and tumors, often in association with increased copy number. Moreover, we demonstrate that antisense-mediated repression of miR-182 inhibited invasion and induced melanoma cell death, whereas ectopic miR-182 up-regulation enhanced the oncogenic activity of melanoma cells in vitro ...

Squamous cell carcinomas of the urinary bladder are rare in the Western world; the majority of cases are reported in countries endemic to Schistosoma parasitic infections. Unlike squamous tumors of the uterine cervix or oropharynx, the human papillomavirus (HPV) is not commonly associated with bladder squamous cell carcinomas. We report on two cases of HPV-positive urothelial carcinomas of the urinary bladder with extensive squamous differentiation showing the typical basaloid, poorly differentiated morphology of HPV-associated tumors. These occurred in patients with neurogenic bladders who had long-standing histories of selfcatheterization with tumors that tested positive for HPV by in situ hybridization. A retrospective review of our institutional database revealed four additional patients with bladder tumors showing squamous differentiation arising in the setting of neurogenic bladder. Review of these cases showed the more common welldifferentiated keratinizing appearance of squamous cell carcinomas of the bladder. These tumors showed only patchy positivity for p16 immunohistochemical stain (not the diffuse strong staining seen in HPV-positive tumors), and the one tested case was negative for HPV by in situ hybridization. HPV infection and neurogenic bladder have been independently associated with increased risk of developing carcinoma in the urinary bladder; however, this is the first report of squamous tumors arising in the setting of concurrent neurogenic bladder and HPV infection. The morphology of these tumors is similar to that of other high-risk HPV-associated squamous carcinomas with a basaloid, poorly differentiated appearance and little to no keratin formation. Modern Pathology (2012) 25, 1534-1542; doi:10.1038/modpathol.2012.112; published online 6 July 2012 Keywords: HPV; neurogenic bladder; squamous cell carcinoma; urothelial cancerThe human papillomavirus (HPV) has an important role as a human carcinogen, with an estimated 10% of cancers worldwide attributed to it. 1 HPV is a small circular double-stranded DNA virus with more than 100 different types described to date. 2 The potential of the virus to cause malignant or benign lesions dictates its classification into low-risk (6,11,40,42, and so on) or high-risk (16,18,31,33,45,51, and so on) types. The prototypical model for carcinogenesis is squamous cell carcinoma of the uterine cervix, in which nearly all such carcinomas are associated with HPV infection. 3,4 The oncogenic role of HPV is also well established for a subset of squamous cell carcinomas in the vulva, 5 penis, 6 anus, 7 and oropharynx. 8 The possible role of HPV infection in bladder tumors has not been completely elucidated as HPV detection rates vary widely from 0 to 100%, depending on the study. 9,10 An intriguing issue has been the possible association of the virus with bladder squamous cell carcinoma. The few published studies 11-14 on this relationship have shown a low frequency of HPV detection, implying that HPV is not likely to have a major role in the development of bladd...

BRCAX cancers in our cohort (27 ⁄ 39, 69%) showed cyclin D1 immunopositivity compared with Colombo et al. (12 ⁄ 33, 36%). No significant difference in cyclin D1 expression was present between BRCA2 and BRCAX cancers (P = 0.917). For BRCA2 and BRCAX cancers that were positive for cyclin D1, similar proportions of cancers was also positive for ER [14 ⁄ 16 (88%) and 19 ⁄ 24 (79%), respectively, P = 0.497].The difference in cyclin D1 expression may be due to the higher number of grade 3 tumours in our BRCAX cohort (51%). This is higher than that found in the cohort of Colombo et al. (24%) and in the larger BRCAX cohort of Aaltonen et al. 3 (27%). Nevertheless, the proportion of BRCAX cancers that were immunohistochemically positive for cyclin D1 in our study is closer to the 55% obtained by Aaltonen et al. 3 in a larger cohort of 456 familial BRCAX cancers, and similar to data available for sporadic breast cancers (50-78%). 4,5 Furthermore, a similar proportion of cyclin D1-positive BRCA2 and BRCAX cancers were also positive for ER in our series. This suggests that grade may not account for the discrepancy. Other possible differences in cyclin D1 expression in our cohort may be due to differences in antigen retrieval, antibody clone, dilution and intensity cut-offs used.While the number of BRCAX cases in our study was limited, there was no significant difference in cyclin D1 expression between BRCA2 and BRCAX cancers. Further studies may be required to evaluate fully the use of cyclin D1 to differentiate between BRCA2 and BRCAX cancers, and we would suggest caution in using cyclin D1 to discriminate between BRCA2 and BRCAX.

Carcinoid tumors are derived from neuroendocrine cells, and are most frequently found in the gastrointestinal tract and bronchopulmonary system. Cutaneous involvement of carcinoid tumors is relatively rare, with isolated case reports in the literature. We detail a patient with stage IV pulmonary atypical carcinoid tumor with skin metastasis. This case is unusual because the patient did not have any erythema or induration of the scalp, only a complaint of pain. On biopsy, the tumor cells had cytologic features of a carcinoid tumor, but were arranged as infiltrating cords, small aggregates and single units, rather than the organoid or trabecular pattern seen in the primary tumor. Further, along with neuroendocrine markers, the tumor cells had the staining pattern of cytokeratin 7+/cytokeratin 20-/thyroid transcription factor-1+, supporting a carcinoid tumor of lung origin. Thus, this case of skin metastasis from an atypical pulmonary carcinoid tumor illustrates a unique clinical and histologic presentation.

Extraneural metastases of ependymoma are rare, and have been reported in the lungs, lymph nodes, pleura, mediastinum, liver, diaphragmatic muscle, and bone. We report a case of anaplastic ependymoma with distant metastases to the vertebral bones, lungs, liver, and lymph nodes following treatment with bevacizumab. Recent research has hypothesized that angiogenic tumors may develop means of resistance to antiangiogenic therapies, and some evidence suggests potential for antiangiogenic therapies to promote additional means for cancer spread. Nevertheless, antiangiogenic therapies continue to demonstrate potential as potent therapies for the treatment of many cancers, and should continue to be researched for future uses.