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View the Table of Contents for the December 1 issue of Cancer Research.
Oda et al. Page 10669 Isakoff et al. Page 10992 Frattini et al. Page 11227
Both inactivation of PTEN gene and mutation of the catalytic subunit alpha of PIK3 (PIK3CA) are involved in activation of PI3K pathway. However, the coexistence of mutations in these two genes has been thought to be exceedingly rare. Oda et al. screened 66 primary endometrial carcinomas and determined that frequency of PIK3CA mutation was 36% and PIK3CA/PTEN double mutations occurred in 26%. Knocking down PTEN expression enhanced the phosphorylation of Akt in HEC-1B cells with K-Ras and PIK3CA mutations, suggesting that double mutation of PIK3CA and PTEN has an additive effect on PI3K activation. Frattini et al. analyzed 60 CRC cases and found 12 carrying PI3KCA mutations. All the cases (12/12=100%) carrying PIK3CA mutations were PTEN positive. On the contrary, among tumors without PIK3CA mutation, only 50% showed PTEN immunodecoration (p=0.001728). Isakoff et al. generated MCF-10A cells harboring mutations in PIK3CA. Mammary epithelial cells expressing the mutant p110a exhibited increased PI3K activity, anchorage-independent proliferation, growth factor-independent proliferation, and protection from anoikis. Furthermore, PIK3CA mutations induced abnormal mammary acinar morphogenesis in 3D basement membrane cultures and conferred increased resistance to paclitaxel.
Cai et al. Page 10912
In order for a cell to accumulate sufficient genetic defects to become cancer, it must acquire a mechanism for avoiding apoptosis. Fas Ag signaling is often lost in gastric cancer; however, it is not clear if this is an early or late event in cancer formation. To explore its role in gastric cancer, Cai et al. developed a Fas Ag deficient chimeric mouse and tested this model’s response to Helicobacter infection, a known gastric carcinogen. Fas-deficient mice developed numerous early and aggressive gastric cancer lesions compared to wild-type mice. Identifying an early signaling defect in gastric cancer offers new targets for prevention and cancer therapy.
Collins et al. Page 10946
Recent reports of cancer stem cells have prompted questions regarding the involvement of normal stem/progenitor cells in prostate tumor biology, their potential contribution to the tumor, and whether they are the cause of tumor initiation and progression. Collins et al. have isolated a minority population of human prostate cancer cells based on the expression of the cell surface markers α2β1 and CD133. α2β1hi/CD133+ cells displayed stem cell-like properties: The generation of new clones containing additional stem cells, as well as phenotypically mixed populations of nonclonogenic cells present in the original tumors. The identification of a prostate cancer stem cell provides a powerful tool to investigate how the cancer stem cell differs from the normal stem cell, which might allow it to be selectively targeted and eliminated, improving therapeutic outcome.
Even though epidemiological and animal studies implicate estrogen in cervical cancer, there is no direct evidence for the involvement of local estrogen in this process. Nair et al. found that about 35% of cervical carcinomas express aromatase, the enzyme responsible for estrogen biosynthesis. No aromatase expression was detected in precancerous or normal cervical tissue samples suggesting the importance of local estrogen in cervical carcinogenesis. This novel report demonstrates the induction of aromatase expression in some cervical carcinomas and opens the possibility of potential targeted use for aromatase inhibitors in the treatment and prevention of cervical cancers. Ma et al. “resequenced” the human CYP19 gene in DNA samples from Caucasian-American, African-American, Han Chinese-American and Mexican-American subjects and identified 88 polymorphisms with striking ethnic-dependent variation. These observations can now be used to test the hypothesis that genetic variation in CYP19 may contribute to risk for diseases such as breast cancer, or individual variation in response to aromatase inhibitors.
Albers et al. Page 11146
Human papillomavirus (HPV)–encoded oncogenic proteins, such as E7, appear to be useful targets for immunotherapy of HPV+ squamous cell carcinoma of the head and neck (SCCHN). To characterize the endogenous immune response to HPV-16 E7, Albers et al. analyzed the frequency and phenotype of circulating E7-specific T cells in SCCHN patients, which persist despite active tumor burden. In addition to phenotypic effector T-cell abnormalities, the studies revealed evidence of down-regulation of antigen-processing machinery in HPV-infected SCCHN cells despite detectable expression of the restricting HLA allele. Reversal of these APM component defects by IFN-γ treatment led to E7-specific CTL recognition of an HPV+ SCCHN cell line. These findings suggest further development of E7-specific T-cell immunotherapy and strategies for up-regulation of APM component expression in HPV-associated SCCHN.