Ectopic activation of the Wnt signaling pathway is highly oncogenic for many human tissues. Here, we show that ectopic Wnt signaling increases the effective stem cell activity in mouse mammary glands in vivo. Furthermore, Wnt effectors induce the accumulation of mouse mammary epithelial progenitors (assayed by Hoechst dye exclusion, a surrogate stem cell marker, side population cells) both in vivo and in vitro. The longevity of stem cells makes them good candidate tumor precursors, and we propose that Wnt-induced progenitor amplification is likely to be key to tumor initiation. In support of this notion, mammary glands from a tumor-resistant strain of mice (carrying a null mutation in syndecan-1) contain fewer side population cells. When this strain is crossed to mice that overexpress effectors of the ␤-catenin͞T cell factor Wnt pathway, the amplification of progenitors is reduced, together with all subsequent events of tumor development. We propose that the growth dynamic of the stem cell fraction is a major determinant of tumor susceptibility.Wnt-1 ͉ ␤-catenin ͉ syndecan-1 ͉ heparan sulfate proteoglycan ͉ mouse mammary epithelial cells

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We previously showed that mice with a null mutation in syndecan-1 (Sdc1; CD138) were resistant to Wnt1-induced mammary tumor initiation. The absence of Sdc1 inhibited the increase in the mammary stem cell fraction that is characteristic of preneoplasia in this model. As the tumor precursor cells are recruited from the stem/ progenitor cell compartment, tumor development was also inhibited (Liu et al., 2004; PNAS 101, 4158). Although Sdc1À/À mice are grossly normal, they are systemically smaller, suggesting that developmental abnormalities may extend further than their mammary glands. We have therefore evaluated the multi-organ response of Sdc1À/À mice to carcinogen-induced tumor development (7,12-dimethylbenz[a]anthracene, DMBA), and find these mice to be resistant to tumorigenesis in all the predominant carcinogen-susceptible lineages. Thus, Sdc1À/À mice administered DMBA during juvenile development are resistant not only to epithelial tumors, including liver (60-80%) and lung tumors (C57BL6 mice, 60-80%), but also to lymphoma (over 70%, depending upon strain and carcinogen dose). We demonstrate that CD138 is expressed (heterogeneously) in the hematopoietic stem cell fraction (and not only in pre-B and plasma cells), and that tumors arise in both myeloid and lymphoid lineages. Furthermore, carcinogen-induced mammary tumors are bilineal, implying a bipotent precursor cell. Both observations imply that the DMBA-induced tumor precursor cells are drawn from the stem/progenitor fraction, and we suggest that pathogenic activation of these cells could be abnormal in Sdc1À/À mice.

Identification of novel prognostic biomarkers typically requires a large dataset which provides sufficient statistical power for discovery research. To this end, we took advantage of the high‐throughput data from The Cancer Genome Atlas (TCGA) to identify a set of prognostic biomarkers in head and neck squamous cell carcinomas (HNSCC) including oropharyngeal squamous cell carcinoma (OPSCC) and other subtypes. In this study, we analyzed miRNA‐seq data obtained from TCGA patients to identify prognostic biomarkers for OPSCC. The identified miRNAs were further tested with an independent cohort. miRNA‐seq data from TCGA was also analyzed to identify prognostic miRNAs in oral cavity squamous cell carcinoma (OSCC) and laryngeal squamous cell carcinoma (LSCC). Our study identified that miR‐193b‐3p and miR‐455‐5p were positively associated with survival, and miR‐92a‐3p and miR‐497‐5p were negatively associated with survival in OPSCC. A combined expression signature of these four miRNAs was prognostic of overall survival in OPSCC, and more importantly, this signature was validated in an independent OPSCC cohort. Furthermore, we identified four miRNAs each in OSCC and LSCC that were prognostic of survival, and combined signatures were specific for subtypes of HNSCC. A robust 4‐miRNA prognostic signature in OPSCC, as well as prognostic signatures in other subtypes of HNSCC, was developed using sequencing data from TCGA as the primary source. This demonstrates the power of using TCGA as a potential resource to develop prognostic tools for improving individualized patient care.

Objective To study osteoradionecrosis (ORN) of the temporal bone Study Design Retrospective case review Setting Academic medical center Patients Patients were included who had previously undergone radiation to the head and neck and then developed exposed necrotic bone within the ear canal that persisted at least three months Intervention(s) Patients were treated with a variety of modalities, including conservative therapy with antibiotic ear drops and in-office debridements, hyperbaric oxygen therapy and surgery. Main Outcome Measure(s) To describe the presentation and management of patients with temporal bone osteoradionecrosis. Results 33 patients with temporal bone osteoradionecrosis were included. The most common site of primary tumor was the parotid gland (n=11), followed by the nasopharynx (n=7). The time to development of ORN varied between 1 and 22 years, with mean 7.9 years. The mean radiation dose was 62.6 Gy to the primary tumor, 53.1 Gy to the affected temporal bone, and 65.2 Gy to the affected tympanic bone. The most common symptoms of ORN were otorrhea (n=15), hearing loss (n=13), and otalgia (n=12). 15 patients had bacterial superinfection, most commonly S. aureus (n=9). Conservative therapy was successful at managing symptoms but not in eradicating exposed bone in most patients. Surgery was used for recalcitrant pain, infection, cholesteatoma, cranial neuropathies, and intracranial complications. Conclusions Osteoradionecrosis is a rare complication of radiation to the temporal bone. Management should be aimed at relief of symptoms, eradication of superinfection, and treatment of other commonly present radiation effects like cholesteatoma and hearing loss.