Aging, cancer, and cancer vaccines

ABSTRACT: World population has experienced continuous growth since 1400 A.D. Current projections show a continued increase - but a steady decline in the population growth rate - with the number expected to reach between 8 and 10.5 billion people within 40 years. The elderly population is rapidly rising: in 1950 there were 205 million people aged 60 or older, while in 2000 there were 606 million. By 2050, the global population aged 60 or over is projected to expand by more than three times, reaching nearly 2 billion people 1. Most cancers are age-related diseases: in the US, 50% of all malignancies occur in people aged 65-95. 60% of all cancers are expected to be diagnosed in elderly patients by 2020 2. Further, cancer-related mortality increases with age: 70% of all malignancy-related deaths are registered in people aged 65 years or older 3. Here we introduce the microscopic aspects of aging, the pro-inflammatory phenotype of the elderly, and the changes related to immunosenescence. Then we deal with cancer disease and its development, the difficulty of treatment administration in the geriatric population, and the importance of a comprehensive geriatric assessment. Finally, we aim to analyze the complex interactions of aging with cancer and cancer vaccinology, and the importance of this last approach as a complementary therapy to different levels of prevention and treatment. Cancer vaccines, in fact, should at present be recommended in association to a stronger cancer prevention and conventional therapies (surgery, chemotherapy, radiation therapy), both for curative and palliative intent, in order to reduce morbidity and mortality associated to cancer progression.     

Mammalian metallothionein in toxicology,cancer, and cancer chemotherapy

The present paper centers on mammalian metallothionein 1 and 2 in relationship to cell and tissue injury beginning with its reaction with Cd²⁺ and then considering its role in the toxicology and chemotherapy of both metals and non-metal electrophiles and oxidants. Intertwined is a consideration of MTs role in tumor cell Zn²⁺ metabolism. The paper updates and expands on our recent review by Petering et al. (Met Ions Life Sci 5:353–398, 2009).     

Environment, inflammation, and cancer

Rudolf Virchow postulated that a critical feature of tumors was the presence of leukocytes, providing the first indication that inflammation may play a role in tumorigenesis. We now have a wealth of experimental and clinical data demonstrating a clear relationship between inflammatory responses and the roles they play at different stages of tumor development. The details of the dynamic relationship between tumor cells and specific subtypes of immune cells and mesenchymal cells are being revealed as critical to cancer progression which has led to the development of potential new targets for cancer treatment. This review describes some of the key molecular and cellular events demonstrating the critical role of inflammation on promoting tumorigenesis with attention on novel therapeutics and their potential clinical success.     

Sex,immunity, and cancer

The composition of the tumor microenvironment is the complex result of the interaction between tumoral and host factors. Since there are several differences in the regulation of gene circuits between sexes, mainly influenced by sex hormones, the tumor-host interaction presents some differences, leading tumors to evolve under different conditions. Nowadays, it is well known the existence of sexual dimorphism in the regulation of the immune system, where women present an improved immunity to various infectious agents and, on the other hand, a higher incidence of autoimmune diseases than men. In oncology, differences in cancer susceptibility, response to treatment, and clinical outcomes between men and women patients are well known. Recently, sex-specific differences have also been reported in mutations in driver genes and the prognostic value of several biomarkers. Sex has been a widely forgotten biomarker in cancer therapy, but it has recently acquired great relevance due to the different results seen in immunotherapy treatment.     

HIFs,angiogenesis, and cancer

Tumor hypoxia was first described in the 1950s by radiation oncologists as a frequent cause of failure to radiotherapy in solid tumors. Today, it is evident that tumor hypoxia is a common feature of many cancers and the master regulator of hypoxia, hypoxia‐inducible factor‐1 (HIF‐1), regulates multiple aspects of tumorigenesis, including angiogenesis, proliferation, metabolism, metastasis, differentiation, and response to radiation therapy. Although the tumor hypoxia response mechanism leads to a multitude of downstream effects, it is angiogenesis that is most crucial and also most susceptible to molecular manipulation. The delineation of molecular mechanisms of angiogenesis has revealed a critical role for HIF‐1 in the regulation of angiogenic growth factors. In this article, we review what has been described about HIF‐1: its structure, its regulation, and its implication for cancer therapy and we focus on its role in angiogenesis and cancer. J. Cell. Biochem. 114: 967–974, 2013. © 2012 Wiley Periodicals, Inc.     

Genes,dreams, and cancer.

There have been tremendous advances in our understanding of cancer from the application of molecular biology over the past decade. The disease is caused by a series of defects in the genes that accelerate growth--oncogenes--and those that slow down cellular turnover--tumour suppressor genes. The proteins they encode provide a promising hunting ground in which to design and test new anticancer drugs. Several treatment strategies are now under clinical trial entailing direct gene transfer. These include the use of gene marking to detect minimal residual disease, the production of novel cancer vaccines by the insertion of genes which uncloak cancer cells so making them visible to the host''s immune system, the isolation and coupling of cancer specific molecular switches upstream of drug activating genes, and the correction of aberrant oncogenes or tumour suppressor genes. The issues in these approaches are likely to have a profound impact on the management of cancer patients as we enter the next century.     

Pancreatic cancer,stroma, and exosomes

Journal of Physiology and Biochemistry - In the pathogenesis of pancreatic adenocarcinoma, tumor stroma plays a key role in both aggressiveness, immune evasion, resistance to chemotherapy, and the...     

Statins,stem cells,and cancer

The statins (3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors) were proven to be effective antilipid agents against cardiovascular disease. Recent reports demonstrate an anticancer effect induced by the statins through inhibition of cell proliferation, induction of apoptosis, or inhibition of angiogenesis. These effects are due to suppression of the mevalonate pathway leading to depletion of various downstream products that play an essential role in cell cycle progression, cell signaling, and membrane integrity. Recent evidence suggests a shared genomic fingerprint between embryonic stem cells, cancer cells, and cancer stem cells. Activation targets of NANOG, OCT4, SOX2, and c‐MYC are more frequently overexpressed in certain tumors. In the absence of bona fide cancer stem cell lines, human embryonic stem cells, which have similar properties to cancer and cancer stem cells, have been an excellent model throwing light on the anticancer affects of various putative anticancer agents. It was shown that key cellular functions in karyotypically abnormal colorectal and ovarian cancer cells and human embryonic stem cells are inhibited by the statins and this is mediated via a suppression of this stemness pathway. The strategy for treatment of cancers may thus be the targeting of a putative cancer stem cell within the tumor with specific agents such as the statins with or without chemotherapy. The statins may thus play a dual prophylactic role as a lipid‐lowering drug for the prevention of heart disease and as an anticancer agent to prevent certain cancers. This review examines the relationship between the statins, stem cells, and certain cancers. J. Cell. Biochem. 106: 975–983, 2009. © 2009 Wiley‐Liss, Inc.     

Microcalcifications,calcium-sensing receptor,and cancer

Calcium stones and calculi are observed in numerous human tissues. They are the result of deposition of calcium salts and are due to high local calcium concentrations. Prostatic calculi are usually classified as endogenous or extrinsic stones. Endogenous stones are commonly caused by obstruction of the prostatic ducts around an enlarged prostate resulting from benign prostatic hyperplasia or from chronic inflammation. The latter occurs mainly around the urethra and is generally caused by reflux of urine into the prostate. Calcium concentrations higher than in the plasma at sites of infection may induce the chemotactic response that eventually leads to recruitment of inflammatory cells. The calcium sensing receptor (CaSR) may be crucial for this recruitment as its expression and activity are increased by cytokines such as IL-6 and high extracellular calcium concentrations, respectively. The links between calcium calculi, inflammation, calcium supplementation, and CaSR functions in prostate cancer patients will be discussed in this review.     

Nitrite, nitrosamines, and cancer.

Carcinogenic N-nitroso compounds are formed from the reaction of naturally-occurring amines and nitrites that may be added to foods or produced by bacterial reduction of nitrate. N-Nitroso compounds can be produced during processing, storage and preparation of foods and in the mammalian stomach. Factors that influence the rates of nitrosation reactions include pH, temperature, catalysts, and inhibitors. Predictions of the extent of nitrosation are complicated by these factors and ultimately the amounts and types of N-nitroso compounds present must be determined by direct analysis. Methods for detection and estimation of volatile nitrosamines are available and low levels (parts per billion) have been found in some cured meat and fish products. General methods for detection of all N-nitroso compounds are not available yet, but are under development. Evaluation of the risk to human populations from these compounds is difficult in the absence of more comprehensive data on their environmental distribution.     

Breast cancer,lactation, and genetics

Abstract

A review of mortality rates from breast cancer in several nations indicates that most Caucasian populations have higher rates than do most non‐Caucasian. The only environmental factor shown to affect breast cancer rates consistently is parity, and its mechanisms of actuation are unknown. The higher risks of breast cancer among relatives of patients are reviewed, and a multifactorial genetic control is assumed in which the effects of genetic and environmental factors may be in part additive. While genetic effects are evident in both breast cancer and lactation, it is not clear whether they depend on two distinct sets of genetic factors or on a single set. Assuming that the higher frequencies of breast cancer in Caucasian populations are in some way associated with abnormal genetic factors in hypolactation, the hypothesis is suggested that their rate of elimination by natural selection might have become relaxed or diminished in remote prehistoric times only in Caucasian populations through their widespread development of domestic animal milk as an artificial infant food. Relaxed selection of genetic factors for hypolactation might have caused them to accumulate among Caucasian populations in sufficient frequencies to produce appreciably higher rates of breast cancer in these populations today, even where breast‐feeding is the rule.     

Differentiation, cancer, and anticancer activity

Carcinogenesis is a multistep process that results from the development of a variety of defects in the control of differentiation and proliferation. To investigate this concept further, 3T3 T mesenchymal stems cells were employed to establish that a distinct sequence of biological processes is involved in the control of differentiation and proliferation, and that these processes are integrally regulated. Specific defects in these regulatory processes were next established as being involved in carcinogenesis. These defects, however, were found not to be absolute; rather, they appear to involve changes in the stringency by which differentiation and proliferation are integrally regulated. Finally, it was established that when normal or transformed stem cells are induced to undergo nonterminal differentiation (which is one step in the integrated control of proliferation and differentiation), they can be made resistant to carcinogenesis or to revert to a nontransformed state. These data provide strong evidence that a critically important requirement for normal homeostasis is maintenance of intact cellular mechanisms to integrally regulate differentiation and proliferation.     

Immunity,ageing and cancer

Compromised immunity contributes to the decreased ability of the elderly to control infectious disease and to their generally poor response to vaccination. It is controversial as to how far this phenomenon contributes to the well-known age-associated increase in the occurrence of many cancers in the elderly. However, should the immune system be important in controlling cancer, for which there is a great deal of evidence, it is logical to propose that dysfunctional immunity in the elderly would contribute to compromised immunosurveillance and increased cancer occurrence. The chronological age at which immunosenescence becomes clinically important is known to be influenced by many factors, including the pathogen load to which individuals are exposed throughout life. It is proposed here that the cancer antigen load may have a similar effect on "immune exhaustion" and that pathogen load and tumor load may act additively to accelerate immunosenescence. Understanding how and why immune responsiveness changes in humans as they age is essential for developing strategies to prevent or restore dysregulated immunity and assure healthy longevity, clearly possible only if cancer is avoided. Here, we provide an overview of the impact of age on human immune competence, emphasizing T-cell-dependent adaptive immunity, which is the most sensitive to ageing. This knowledge will pave the way for rational interventions to maintain or restore appropriate immune function not only in the elderly but also in the cancer patient.     

Telomeres, crisis and cancer

Eukaryotic chromosomes terminate in specialized nucleic acid-protein complexes known as telomeres. Disruption of telomere structure by erosion of telomeric DNA or loss of telomere binding protein function activates a signal transduction program that closely resembles the cellular responses generated upon DNA damage. Telomere dysfunction in turn induces a permanent proliferation arrest known as senescence. Senescence is postulated to perform a tumor suppressor function by limiting cellular proliferative capacity, thus imposing a barrier to cellular immortalization. Genetic or epigenetic silencing of components of the DNA damage pathway, allows cells to proliferate beyond senescence limits. However, these cells eventually reach a stage of extreme telomere dysfunction known as crisis that is characterized by cell death and the concomitant appearance of cytogenetic abnormalities. Telomeric crisis produces significant chromosomal instability, a hallmark of human cancer, and may thus be relevant to carcinogenesis by increasing the occurrence of genetic alterations that would favor neoplastic transformation. The following review examines the relationship of telomere function during crisis in accelerating chromosomal instability and cancer.     

Music,immunity and cancer

The effects of music on the immune system and cancer development were evaluated in rodents subjected to sound stress. Animals were exposed daily to broad band noise around midnight and/or music for 5 hours on the following morning. Thymus and spleen cellularity, peripheral T lymphocyte population, the proliferative response of spleen cells to mitogen concanavalin A and natural killer cell activity were calculated in BALB/c mice. Sprague Dawley rats were injected i.v. with Walker 256 carcinosarcoma cells; 8 days later the rats were sacrificed and the number of metastatic nodules on the surface of the lungs was calculated macroscopically. Music reduced the suppressive effects of stress on immune parameters in mice and decreased the enhancing effects of stress on the development of lung metastases provoked by carcinosarcoma cells. Music enhanced the immune parameters and the anti-tumor response in unstressed rodents. Our data at present demonstrates that music can effectively reverse adverse effects of stress on the number and capacities of lymphocytes that are required for an optimal immunological response against cancer in rodents.