See article by Herrero et al., p. 408.

  • A large clinical and epidemiologic study informs cervical cancer prevention efforts.

  • Vaccine efficacy against HPV16/18 infection is higher than 90%.

  • The benefit of HPV vaccination diminishes with age and sexual experience.

Human papillomavirus (HPV) vaccination of adolescent girls has become a key strategy in developed countries for the prevention of cervical cancer. However, the vast majority of cervical cancer cases occur in developing countries, where prevention and treatment strategies remain controversial due to economic and cultural issues. Herrero and colleagues now report the results of a unique clinical trial of Cervarix (GlaxoSmithKline Biologicals), a vaccine developed to prevent persistent infection with HPV types 16 and 18, which underlies 70% of all cervical cancers. One of the first public HPV vaccine clinical trials, the study was conducted over the past several years in Guanacaste, a region of northwestern Costa Rica with a traditionally high incidence of cervical cancer. In addition to the size, homogeneity, and stability of the population analyzed, a distinguishing feature of this study was the use of a 1-year persistent oncogenic infection to determine vaccine efficacy, a more reproducible endpoint than previously used histologic criteria. The vaccine efficacy was higher than 90% in women who were HPV-negative prior to vaccination and complied with the vaccination protocol. When all women were analyzed, however, only approximately half were protected. Vaccine efficacy declined sharply with age and was negatively correlated with both the time since first sexual intercourse and the number of sexual partners. The results of this trial demonstrate the importance of early HPV vaccination in developing populations for the prevention of cervical cancer.

See article by Spitz et al., p. 420.

  • Inflammation pathway gene sequences were evaluated in never smokers with NSCLC.

  • An ACVR1B variant is associated with cancer risk in never smokers exposed to second-hand smoke.

  • ACVR1B encodes a TGF-β receptor and is mutated in other cancer types.

Smoking-associated lung cancer is etiologically and epidemiologically distinct from cancer occurring in patients who have never smoked (never smokers), but the distinguishing molecular features are unclear. Because chronic tobacco-induced inflammation is believed to contribute to lung carcinogenesis, Spitz and colleagues characterized the contribution of inflammatory response gene variants to cancer susceptibility in two case–control studies of never smokers with non–small cell lung cancer (NSCLC). Using a customized Illumina single-nucleotide polymorphism (SNP) chip, the authors genotyped a comprehensive panel of germline genetic variants including 11,737 SNPs associated with inflammation pathway genes. One SNP, within an intron of the Activin receptor type 1B (ACVR1B) gene, achieved statistical significance in both cohorts, particularly when the patients were stratified by environmental tobacco exposure (ETS, or second-hand smoke). ACVR1B is a TGF-β superfamily receptor that, upon binding by activins or activin-like ligands, recruits and activates SMAD proteins to regulate the inflammatory response. Interestingly, differential expression of ACVR1B has previously been observed in epithelial cells and micrometastases from lung cancer patients, and ACVR1B mutations have been identified in pancreatic adenocarcinomas. These findings suggest a provocative link between inflammation and susceptibility to the effects of second-hand smoke.

See article by Novitskiy et al., p. 430.

  • IL-17–dependent CXCL1/5 secretion increases recruitment of MDSCs in Tgfbr2-deficient tumors.

  • Myeloid cells induce differentiation of naïve CD4 cells into Th17 cells, which secrete IL-17.

  • IL-17 stimulates further chemokine secretion and enhances immune suppression by MDSCs.

Decreased TGF-β receptor II (TGFBR2) expression correlates with risk and formation of invasive breast cancer, and Tgfbr2 deletion in murine mammary epithelial cells promotes tumor formation and metastasis. Novitskiy and colleagues previously noted an increase in myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM) in the murine tumors, which facilitate tumor progression by suppressing the immune response to cancer cells. In this study, they show that MDSC recruitment to tumors is dependent on increased secretion of the cytokines CXCL1 and CXCL5 in the absence of Tgfbr2. MDSCs and TAMs then stimulate differentiation of naïve CD4 cells into Th17 cells, helper T cells that secrete interleukin 17 (IL-17). IL-17 induces further chemokine secretion by the tumors, resulting in additional myeloid cell recruitment. IL-17 also augments tumor immune evasion by upregulating genes in MDSCs that mediate their ability to suppress T-cell proliferation, suggesting that this cytokine plays a central role in tumor immune evasion and progression of breast cancers. Indeed, the authors show that an IL-17 antibody suppressed the growth and metastasis of Tgfbr2-deficient tumors and that IL-17 gene expression is negatively correlated with TGF-β pathway activation and associated with a lower relapse-free survival in breast cancer patients. These findings suggest that targeting IL-17 may promote immune surveillance of tumor cells and represent a therapeutic alternative to modulation of TGF-β signaling in breast cancer.

See article by Guo et al., p. 442.

  • EGFR, PI3K-dependent LDLR activation constitutes a cancer survival pathway.

  • EGFR mutations increase GBM dependence on cholesterol intake.

  • LXR agonists inhibit growth and induce apoptosis in GBM xenografts.

Cancer cells exhibit altered energy metabolism to meet the biosynthetic demands of rapid proliferation, but the particular role of cholesterol uptake, efflux, and synthesis in tumorigenesis is not well understood. Cholesterol is required for biogenesis of cell membranes and is a key component of lipid rafts, specialized plasma membrane microdomains that organize signaling molecules. Guo and colleagues therefore hypothesized that limiting cholesterol levels would inhibit proliferation of rapidly dividing cancer cells. Because the authors had previously demonstrated that an EGFR-PI3K signaling axis promotes lipogenesis, a process closely related to cholesterol synthesis, they focused on glioblastoma multiforme (GBM), nearly 90% of which exhibit hyperactive PI3K signaling due to EGFR mutation or PTEN loss. EGFR/PI3K-dependent low-density lipoprotein receptor (LDLR) upregulation was observed in GBM cell lines, xenografts, and patient samples. Furthermore, depletion of extracellular cholesterol inhibited the proliferation of EGFR-mutant GBM cells, suggesting that targeting cholesterol metabolism may be a potential therapeutic strategy. Indeed, pharmacologic activation of the liver X receptor (LXR), which normally responds to excess cholesterol by promoting LDLR degradation and cholesterol efflux, inhibits GBM cell proliferation and tumor growth in vivo, indicating that LXR agonists may a viable option for treatment of this highly lethal tumor. The identification of subverted cholesterol intake control mechanisms in cancer also provides an explanation for why many tumors are resistant to statins, which only suppress de novo cholesterol synthesis.

Note:In This Issue is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details.