Cancer stem cells (CSCs) have been identified in solid tumors and cancer cell lines. In this study, we isolated a series of cancer cell clones, which were heterogeneous in growth rate, cell cycle distribution and expression profile of genes and proteins, from ovarian tumor specimens of a patient and identified a sub-population enriched for ovarian CSCs defined by CD24 phenotype. Experiments in vitro demonstrated CD24þ sub-population possessed stem celllike characteristics of remaining quiescence and more chemoresistant compared with CD24À fraction, as well as a specific capacity for self-renewal and differentiation. In addition, injection of 5 Â 10 3 CD24 þ cells was able to form tumor xenografts in nude mice, whereas equal number of CD24 À cells remained nontumorigenic. We also found that CD24 þ cells expressed higher mRNA levels of some 'stemness' genes, including Nestin, b-catenin, Bmi-1, Oct4, Oct3/4, Notch1 and Notch4 which were involved in modulating many functions of stem cells, and lower E-cadherin mRNA level than CD24 À cells. Altogether, these observations suggest human ovarian tumor cells are organized as a hierarchy and CD24 demarcates an ovarian cancer-initiating cell population. These findings will have important clinical applications for developing effective therapeutic strategies to treat ovarian cancer.

The prevalence of human papillomavirus (HPV) infection is high in the oropharyngeal mucosal regions, of which the tonsil is the most commonly affected. There may be a link between HPV and the pathogenesis of tonsillar cancer (TC), because of common anatomical characteristics between cervical and tonsillar cancer. We aimed to clarify whether HPV directly affects the oncogenesis and biologic behavior of TC by making a comparison between infection prevalence, physical status and viral loading numbers, and clinicopathologic prognostic factors. To compare HPV-related molecules between TC and tonsillitis (CFT), p16, survivin, HIF-1a, skp-1, cyclin A, cyclin B1, c-myc and EGFR were investigated. We observed a significant difference in HPV prevalence between 52 TCs and 69 CFTs (73.1% vs. 11.6%), and most of the HPVs were type 16 (87.2%) and nonepisomal (94.1%). Most TCs associated with HPV arose from the tonsillar crypts, and tended to be inverted and poorly differentiated. Compared with HPV-negative TC, HPV-positive TC showed a strong association with p16 overexpression (p < 0.0001), and an inverse association with EGFR amplification (p 5 0.0478). HPV-16 integration status was strongly associated with c-myc amplification (p 5 0.034) and HIF-1a overexpression (p 5 0.022). HPV-16 integration could be directly related to tonsillar carcinogenesis initially in tonsillar crypts, followed by cell cycle aberration such as p16 overexpression related to the G1-S phase. ' 2006 Wiley-Liss, Inc.Key words: human papillomavirus; integration; tonsil cancer; p16; epidermal growth factor receptor Human papillomavirus (HPV) may be postulated to play a role in the pathogenesis of palatine tonsillar cancer (TC), not only due to its morphological similarities to cervical cancer but also because the mucosal squamous epithelium, similar to that of the uterine cervix, is easily exposed to viral infection. HPV infection is prevalent in the oropharyngeal mucosal regions, and the tonsil is the most commonly affected anatomical region in the oropharynx.1,2 Furthermore, TC frequently has a verrucous or papillomatous appearance, with tumor cells showing features of HPV infection, namely koilocytotic atypia. However, it remains uncertain whether HPV is directly associated with the malignant transformation of oropharngeal tumors.The molecular biology of viral oncogenesis has been well established. The viral protein E6 promotes the degradation of p53 and E7 inactivates pRb, usually followed by viral integration into the host genome.3,4 For viral integration, disruption occurs most frequently in an E2 open reading frame (ORF), the E1 ORF being disrupted in a minor proportion of patients. Both are important in viral replication and transcription. More specifically, the breakage of E2 allows for the dysregulation of the E6/E7 oncoprotein, which eventually leads to malignant transformation. 5 In the non-integrated episomal state, the transcriptional level of E6/E7 is regulated by a promoter in the long control region in high-risk HPV-infected cells. It is ...

SummaryFibroblasts were extracted from tissue in tumor burden zones, distal normal zones and interface zones between tumor and normal tissue of human breast carcinomas, and the corresponding fibroblasts were designated as cancer-associated fibroblasts (CAFs), normal zone fibroblasts (NFs) and interface zone fibroblasts (INFs). The crosstalk between three types of fibroblasts and breast cancer cells was evaluated using an in vitro direct co-culture model. We found that INFs grew faster and expressed higher levels of fibroblast activation protein than did NFs and CAFs. Compared with CAFs and NFs, INFs grown with breast cancer cells were significantly more effective in inducing an epithelial-mesenchymal transition (EMT) in cancer cells, as indicated by induction of vimentin and N-cadherin and downregulation of E-cadherin. This EMT process was also accompanied by activation of extracellular signal-regulated kinase (ERK) and modulation of membrane-type 1 matrix metalloproteinase (MT1-MMP) expression. Additionally, INFs promoted breast cell migration to a larger extent compared with NFs and CAFs. Taken together, these findings indicate that INFs isolated from the tumor interface zone exhibited more robust biological modulatory activity than did NFs and CAFs isolated from normal and tumor zones of the same tumor tissue, suggesting that the interface zone of the tumor represents a dynamic region vital to tumor progression.

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Primary chemotherapy with epirubicin and cisplatin, although resulting in tumor response in a significant proportion of patients, is accompanied by an inferior local control rate and survival compared with standard pelvic radiotherapy alone.