Summary Acquired resistance to Docetaxel precedes fatality in hormone-refractory prostate cancer (HRPC). However, strategies that target Docetaxel resistant cells remain elusive. Using in vitro and in vivo models, we identified a subpopulation of cells that survive Docetaxel exposure. This subpopulation lacks differentiation markers and HLA class I (HLAI) antigens, while overexpressing the Notch and Hedgehog signaling pathways. These cells were found in prostate cancer tissues and were related to tumor aggressiveness and poor patient prognosis. Notably, targeting Notch and Hedgehog signaling depleted this population through inhibition of the survival molecules AKT and Bcl-2, suggesting a therapeutic strategy for abrogating Docetaxel resistance in HRPC. Finally, these cells exhibited potent tumor-initiating capacity, establishing a link between chemotherapy resistance and tumor progression.

We analyzed the PI3K-AKT signaling cascade in a cohort of sarcomas and found a marked induction of insulin receptor substrate-2 (IRS2) and phosphorylated AKT and a concomitant upregulation of downstream effectors in most leiomyosarcomas. To determine the role of aberrant PI3K-AKT signaling in leiomyosarcoma pathogenesis, we genetically inactivated Pten in the smooth muscle cell lineage by cross-breeding Pten(loxP/loxP) mice with Tagln-cre mice. Mice carrying homozygous deletion of Pten alleles developed widespread smooth muscle cell hyperplasia and abdominal leiomyosarcomas, with a very rapid onset and elevated incidence (approximately 80%) compared to other animal models. Constitutive mTOR activation was restricted to the leiomyosarcomas, revealing the requirement for additional molecular events besides Pten loss. The rapamycin derivative everolimus substantially decelerated tumor growth on Tagln-cre/Pten(loxP/loxP) mice and prolonged their lifespan. Our data show a new and critical role for the AKT-mTOR pathway in smooth muscle transformation and leiomyosarcoma genesis, and support treatment of selected sarcomas by the targeting of this pathway with new compounds or combinations of these with conventional chemotherapy agents.

p63, a member of the p53 gene family, encodes multiple proteins that may either transactivate p53 responsive genes (TAp63) or act as a dominant-negative factor toward p53 and p73 (Delta Np63). p63 is expressed in many epithelial compartments and p63(-/-) mice fail to develop skin, prostate, and mammary glands among other defects. It has been previously shown that p63 is expressed in normal urothelium. This study reports that p63 is regulated in bladder carcinogenesis and that p63 expression is lost in most invasive cancers whereas papillary superficial tumors maintain p63 expression. Examination of bladder carcinoma cell lines reveals that certain lines derived from invasive carcinomas maintain expression of Delta Np63, as demonstrated by both immunoblotting and confirmed by isoform-specific quantitative reverse transcriptase-polymerase chain reaction. Another novel finding reported in this study is the fact that p63(-/-) mice develop a bladder mucosa epithelial layer yet fail to complete uroepithelial differentiation, producing a nontransitional default cuboidal epithelium. These data indicate that in contrast to the skin and prostate, p63 is not required for formation of a bladder epithelium but is indispensable for the specific differentiation of a transitional urothelium.

To identify gene expression changes along progression of bladder cancer, we compared the expression profiles of early-stage and advanced bladder tumors using cDNA microarrays containing 17,842 known genes and expressed sequence tags. The application of bootstrapping techniques to hierarchical clustering segregated early-stage and invasive transitional carcinomas into two main clusters. Multidimensional analysis confirmed these clusters and more importantly, it separated carcinoma in situ from papillary superficial lesions and subgroups within early-stage and invasive tumors displaying different overall survival. Additionally, it recognized early-stage tumors showing gene profiles similar to invasive disease. Different techniques including standard t-test, singlegene logistic regression, and support vector machine algorithms were applied to identify relevant genes involved in bladder cancer progression. Cytokeratin 20, neuropilin-2, p21, and p33ING1 were selected among the top ranked molecular targets differentially expressed and validated by immunohistochemistry using tissue microarrays (n ‫؍‬ 173). Their expression patterns were significantly associated with pathological stage, tumor grade, and altered retinoblastoma (RB) expression. Moreover, p33ING1 expression levels were significantly associated with overall survival. Analysis of the annotation of the most significant genes revealed the relevance of critical genes and pathways during bladder cancer progression, including the overexpression of oncogenic genes such as Transitional cell carcinomas (TCCs) of the bladder define a group of histologically and genetically diverse cancers that account for ϳ4% of all adult malignancies with an annual incidence of ϳ53,200 cases in the United States. Early-stage TCC has been classified into two groups with distinct clinical behavior and different molecular profiles. Superficial low-grade tumors (Ta) are always papillary and may recur but rarely progress, whereas high-grade tumors can be either papillary or flat lesions (Tis) and often progress to invasive disease.2 Clinically, patients diagnosed with localized stage have a 5-year relative survival rate of 93%. However, patients presenting with regional and distant stage have 5-year relative survival rates of 49% and 6%, respectively.1 Among the molecular events that characterize superficial papillary noninvasive bladder tumors are deletions affecting the long arm of chromosome 9, and activation of certain oncogenes, such as H-RAS, alterations identified only in a subset of invasive bladder neoplasms.2 Deletions of 13q at the RB locus and 17p at the TP53 locus, as well as 18q (DCC locus) and 5q (APC locus) losses have been reported in invasive bladder transitional carcinomas, but are absent in papillary noninvasive tumors.2,3 A remaining challenge in bladder cancer is to define targets characteristic of aggressive early-stage tumors before they recur or progress into invasive disease. The present study was designed to identify critical molecular targets altered along the...

The essence and origin of malignant fibrous histiocytoma (MFH) have been debated for now close to five decades. Originally characterized as a morphologically unique soft tissue sarcoma subtype in 1963 of unclear etiology with a following decade and a half of research only to conclude that "the issue of histogenesis [of MFH] is largely unresolvable"; it is "now regarded as synonymous with [high grade] undifferentiated pleomorphic sarcoma [HGUPS] and essentially represents a diagnosis of exclusion". Yet despite this apparent lack of progress, the first decade of the 21 st century has seen some significant progress in terms of defining the origins of MFH. Perhaps more importantly these origins might also pave the way for novel therapies. This manuscript will highlight MFH's troubled history, discuss recent advances, comment as to what the coming years may promise, and what further needs to be done to make sure that progress continues. KeywordsMalignant fibrous histiocytoma (MFH); undifferentiated pleomorphic sarcomas; mesenchymal stem cells; differentiation therapy; classification Classification of SarcomasThere are approximately 12,000 new adult sarcoma cases each year [1], encompassing seventy different histologic types of mesenchymal tumors that arise from bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue. An in depth understanding of the molecular biology for most of these tumor types is unfortunately lacking [2] thus greatly hindering our abilities to develop rational therapeutic options.Cytogenetics has long been used to divide sarcomas into two broad groups [3]: (1) sarcomas with specific genetic alterations and usually simple karyotypes, including reciprocal translocations that result in fusion genes; and (2) sarcomas with nonspecific genetic