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Cancer is an age-associated disease. Although the mechanisms of age-associated increase in cancer incidence are not completely understood, it is believed that the tumor stromal environment significantly influences epithelial malignancy. Fibroblasts are a major cell type in the stroma and, under normal conditions, fibroblasts reside in the quiescent state. Cellular quiescence is a reversible process where cells enter into the proliferative cycle and then exit back to quiescence. We have shown previously that quiescent fibroblasts lose their proliferative capacity as they age, and we defined this mode of cellular aging as chronological life span. Using conditioned media and co-culture experiments, results from this study show that normal human fibroblasts (NHFs) nearing the end of their chronological life span stimulate the proliferation of MB231 and MCF7 human breast epithelial cancer cells. Chemokine C-C motif ligand 5 (CCL5) expression was found to be approximately 8-fold higher in old compared to that in young quiescent NHFs, which correlated with an increase in the ERK1/2-cyclin D1 pro-proliferative pathway in MB231 cells. Conditioned media treated with anti-CCL5 antibody suppressed the activation of the ERK1/2-cyclin D1 pathway and proliferation of MB231 cells. Hydroxytyrosol, a dietary polyphenol and an active ingredient of olive, inhibited CCL5 expression in aging quiescent NHFs. This inhibition was associated with NHFs inability to activate the ERK1/2-cyclin D1 pathway and enhance proliferation of MB231 cells. These results show that fibroblasts nearing the end of their chronological life span promote proliferation of human breast epithelial cancer cells and dietary polyphenols inhibit this process.

Background: Testicular germ cell tumors (GCTs) represent the most common malignancy in young men. While GCTs represent a model for curable solid tumors due to exquisite chemosensitivity, mortality for patients with GCT comprises the most life years lost for non-pediatric malignancies. Given limited options for patients with platinum-resistant disease, improved insight into GCT biology could identify novel therapeutic options for patients with platinum-resistant disease. Recent studies into molecular characteristics of both early stage and advanced germ cell tumors suggest a role for rationally targeted agents and potentially immunotherapy. Recent developments: Recent GWAS meta-analyses have uncovered additional susceptibility loci for GCT and provide further evidence that GCT risk is polygenic. Chromosome arm level amplifications and reciprocal loss of heterozygosity have been described as significantly enriched in GCT compared to other cancer types. Contemporary analyses confirm ubiquitous gain of isochromosome 12 and mutations in addition to previously described GCT-associated genes such as KIT and KRAS. Alterations within the TP53-MDM2 signal transduction pathway appear to be enriched among patients with platinum-resistant disease. Potentially actionable targets, including alterations in TP53-MDM2, Wnt/b-catenin, PI3K, and MAPK signaling, are present in significant proportions of patients with platinum-resistant disease and may be exploited as therapeutic options. Pre-clinical and early clinical data also suggest a potential role for immunotherapy among patients with GCTs. Conclusion: Molecular characterization of GCT patients may provide biologic rationale for novel treatment options in patients with platinum-resistant disease.

Combination radiation and chemotherapy are commonly used to treat locoregionally advanced head and neck squamous cell carcinoma (HNSCC). Aggressive dosing of these therapies is significantly hampered by side effects due to normal tissue toxicity. Selenium represents an adjuvant that selectively sensitizes cancer cells to these treatments modalities, potentially by inducing lipid peroxidation (LPO). This study investigated whether one such selenium compound, methylseleninic acid (MSA), induces LPO and radiation sensitivity in HNSCC cells. Results from 4,4-difluoro-4-bora-3a,4a-diaza-S-indacene (BODIPY) C11 oxidation and ferric thiocyanate assays revealed that MSA induced LPO in cells rapidly and persistently. Propidium iodide (PI) exclusion assay found that MSA was more toxic to cancer cells than other related selenium compounds; this toxicity was abrogated by treatment with α-tocopherol, an LPO inhibitor. MSA exhibited no toxicity to normal fibroblasts at similar doses. MSA also sensitized HNSCC cells to radiation as determined by clonogenic assay. Intracellular glutathione in cancer cells was depleted following MSA treatment, and supplementation of the intracellular glutathione pool with N-acetylcysteine sensitized cells to MSA. The addition of MSA to a cell-free solution of glutathione resulted in an increase in oxygen consumption, which was abrogated by catalase, suggesting the formation of H2O2. Results from this study identify MSA as an inducer of LPO, and reveal its capability to sensitize HNSCC to radiation. MSA may represent a potent adjuvant to radiation therapy in HNSCC.