Cancer and Metastasis Reviews

Angiogenesis is an important mediator of tumor progression. As tumors expand, diffusion distances from the existing vascular supply increases resulting in hypoxia. Sustained expansion of a tumor mass requires new blood vessel formation to provide rapidly proliferating tumor cells with an adequate supply of oxygen and metabolites. The key regulator of hypoxia-induced angiogenesis is the transcription factor hypoxia inducible factor (HIF)-1. Multiple HIF-1 target genes have been shown to modulate angiogenesis by promoting the mitogenic and migratory activities of endothelial cells. Because of this, hypoxia-induced angiogenesis has become an attractive target for cancer therapy, however the mechanisms involved during this process and how best to target it for cancer therapy are still under investigation. This review will cover the current understanding of hypoxia-induced tumor angiogenesis and discuss the caveats of hypoxia-targeted antiangiogenic therapy for the treatment of cancer.

Osteoporosis and other body composition changes are important complications of androgen deprivation therapy (ADT) for prostate cancer. Bilateral orchiectomy and gonadotropin-releasing hormone agonist treatment decrease bone mineral density and increase fracture risk. Other factors including diet and lifestyle may contribute to bone loss in men with prostate cancer. Estrogens play an important role in male bone metabolism. Androgen deprivation therapy with estrogens probably causes less bone loss than bilateral orchiectomy or gonadotropin-releasing hormone agonist treatment. Bicalutamide monotherapy increases serum estrogen levels and may also spare bone. Lifestyle modification including smoking cessation, moderation of alcohol use, and regular weight bearing exercise are recommended to decrease treatment-related bone loss. Supplemental calcium and vitamin D are also recommended. Pamidronate (Aredia®), an intravenous bisphosphonate, prevents bone loss during ADT. Other bisphosphonates are probably effective but have not been studied in hypogonadal men. Androgen deprivation therapy increases fat mass and decreases muscle mass. These body composition changes may contribute to treatment-related decreases in physical capacity and quality of life.

Modulation of histone methylation status is regarded as an important mechanism of epigenetic regulation and has substantial clinical potential for the therapy of diseases, including cancer and other disorders. The present study aimed to provide a comprehensive introduction to the enzymology of histone demethylases, as well as their cancerous roles, molecular mechanisms, therapeutic possibilities, and challenges for targeting them, in order to advance drug design for clinical therapy and highlight new insight into the mechanisms of these enzymes in cancer. A series of clinical trials have been performed to explore potential roles of histone demethylases in several cancer types. Numerous targeted inhibitors associated with immunotherapy, chemotherapy, radiotherapy, and targeted therapy have been used to exert anticancer functions. Future studies should evaluate the dynamic transformation of histone demethylases leading to carcinogenesis and explore individual therapy.

The pediatric peripheral neuroectodermal tumors which include neuroblastoma, peripheral neuroepithelioma and Ewing's sarcoma may correspond to distinct neural crest cell lineages or tumors arrested at different stages of neural crest development. Besides a brief commentary on the salient clinical features of these tumors, this review examines how cell and molecular biological studies have contributed to a re-classification of these tumors. The differentiation of these tumors is reviewed with a particular emphasis on retinoic acid induced differentiation of neuroblastoma as a model to identify genes important in controlling cell growth, suppression of tumorigenicity and induction of differentiation.

Anti-tumor electrochemotherapy, which consists in increasing anti-cancer drug uptake by means of electroporation, is now implanted in about 140 cancer treatment centers in Europe. Its use is supported by the English National Institute for Health and Care Excellence for the palliative treatment of skin metastases, and about 13,000 cancer patients were treated by this technology by the end of 2015. Efforts are now focused on turning this local anti-tumor treatment into a systemic one. Electrogenetherapy, that is the electroporation-mediated transfer of therapeutic genes, is currently under clinical evaluation and has brought excitement to enlarge the anti-cancer armamentarium. Among the promising electrogenetherapy strategies, DNA vaccination and cytokine-based immunotherapy aim at stimulating anti-tumor immunity. We review here the interests and state of development of both electrochemotherapy and electrogenetherapy. We then emphasize the potent beneficial outcome of the combination of electrochemotherapy with immunotherapy, such as immune checkpoint inhibitors or strategies based on electrogenetherapy, to simultaneously achieve excellent local debulking anti-tumor responses and systemic anti-metastatic effects.

Prostate brachytherapy has been practiced for nearly 100 years in various forms. However, technological advances over the past 20 years in imaging, computing, and devices have propelled this technique into the mainstream of prostate cancer treatments. A discussion of radiobiology principles is important to the understanding of modern brachytherapy technique. For low risk tumors, brachytherapy may be administered as monotherapy. For high risk tumors combination therapy with external beam therapy is indicated. Androgen ablation therapy is used for hormonal downsizing or for select high risk tumors. Diseases free survival appears similar to that seen with other definitive therapies for clinically localized prostate cancer. The short term morbidity of the procedure includes significant obstructive and irritative voiding symptoms. Future brachytherapy goals are discussed.

Immunization with anti-idiotypic antibodies is a strategy which, with variable success, can be used to elicit or amplify antigen-specific immune response. This article discusses the manipulation of specific idiotypes in anti-tumor immunity, emphasizing the appropriate consideration of genetic restriction, the choice of idiotype specificity, and the route of immunization. Two independent pathways are outlined: One uses anti-idiotypic antibodies to select and amplify tumor-specific T and B cells via their preexisting antigen-specific receptors, and the other uses anti-idiotypes as primary internal image immunogens to elicit immune recognition of determinants shared by the anti-idiotype and by tumor-associated antigens. Both pathways can be manipulated in attempts to favor the generation of anti-tumor effector cells and minimize the elicitation of suppression. Anti-idiotypic immunization can be utilized to induce therapeutic immune reactivity in hosts lacking effective direct anti-tumor responses. By stimulating ‘silent’, or normally suppressed, T and B cell clones, appropriate immunization strategies can circumvent immune regulatory pathways associated with suppressor cells and factors derived from such cells. In these studies, adequate characterization of antitumor idiotype and anti-idiotype specificities is key to the experimental approach to tumor therapy using antibodies. The importance of individual host genetic variation in the specificity and scope of immune response to anti-idiotypic immunoglobulins is unknown, and remains an important potential barrier to therapeutic management.

In the past decade, there has been an increasing interest in applying proteomics to assist in understanding the pathogenesis of ovarian cancer, elucidating the mechanism of drug resistance, and in the development of biomarkers for early detection of ovarian cancer. Although ovarian cancer is a spectrum of different diseases, the strategies for diagnosis and treatment with surgery and adjuvant therapy are similar across ovarian cancer types, increasing the general applicability of discoveries made through proteomics research. While proteomic experiments face many difficulties which slow the pace of clinical applications, recent advances in proteomic technology contribute significantly to the identification of aberrant proteins and networks which can serve as targets for biomarker development and individualized therapies. This review provides a summary of the literature on proteomics’ contributions to ovarian cancer research and highlights the current issues, future directions, and challenges. We propose that protein-level characterization of primary lesion in ovarian cancer can decipher the mystery of this disease, improve diagnostic tools, and lead to more effective screening programs.