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.     

Apoptosis pathways in cancer and cancer therapy

Activation of apoptosis pathways is a key mechanism by which cytotoxic drugs kill tumor cells. Also immunotherapy of tumors requires an apoptosis sensitive phenotype of target cells. Defects in apoptosis signalling contribute to resistance of tumors. Activation of apoptosis signalling following treatment with cytotoxic drugs has been shown to lead to activation of the mitochondrial (intrinsic) pathway of apoptosis. In addition, signalling through the death receptor (extrinsic) pathways, contributes to sensitivity of tumor cells towards cytotoxic treatment. Both pathways converge finally at the level of activation of caspases, the effector molecules in most forms of cell death. In addition to classical apoptosis, non-apoptotic modes of cell death have recently been identified. Mechanisms to overcome apoptosis resistance include direct targeting of antiapoptotic molecules expressed in tumors as well as re-sensitization of previously resistant tumor cells by re-expression of caspases and counteracting apoptotis inhibitory molecules such as Bcl-2 and molecules of the IAP family of endogenous caspase inhibitors. Molecular insights into regulation of apoptosis and defects in apoptosis signalling in tumor cells will provide novel approaches to define sensitivity or resistance of tumor cells towards antitumor therapy and provide new targets for rational therapeutic interventions for future therapeutic strategies.This work was presented at the first Cancer Immunology and Immunotherapy Summer School, 8–13 September 2003, Ionian Village, Bartholomeio, Peloponnese, Greece.     

Autophagy and cancer

Autophagy is a homeostatic and evolutionarily conserved mechanism of self-digestion by which the cells degrade and recycle long-lived proteins and excess or damaged organelles.Autophagy is activated in response to both physiological and pathological stimuli including growth factor depletion,energy deficiency or the upregulation of Bcl-2 protein expression.A novel role of autophagy in various cancers has been proposed.Interestingly,evidence that supports both a positive and negative role of autophagy in the pathogenesis of cancer has been reported.As a tumor suppression mechanism,autophagy maintains genome stability,induces senescence and possibly autophagic cell death.On the other hand,autophagy participates in tumor growth and maintenance by supplying metabolic substrate,limiting oxidative stress,and maintaining cancer stem cell population.It has been proposed that the differential roles of autophagy in cancer are disease type and stage specific.In addition,substrate selectivity might be involved in carrying out the specific effect of autophagy in cancer,and represents one of the potential directions for future studies.     

Epigenetics and cancer

Epigenetics is defined as "the study of mitotically and/or meiotically heritable changes in gene expression that cannot be explained by changes in the DNA sequence". Setting up the epigenetic program is crucial for correct development and its stable inheritance throughout its lifespan is essential for the maintenance of the tissue- and cell-specific functions of the organism. For many years, the genetic causes of cancer have hold centre stage. However, the recent wealth of information about the molecular mechanisms which, by modulating the chromatin structure, can regulate gene expression has high-lighted the predominant role of epigenetic modifications in the initiation and progression of numerous pathologies, including cancer. The nucleosome is the major target of these epigenetic regulation mechanisms. They include a series of tightly interconnected steps which starting with the setting ("writing") of the epigenetic mark till its "reading" and interpretation will result in long-term gene regulation. The major epigenetic changes associated with tumorigenesis are aberrant DNA methylation of CpG islands located in the promoter region of tumor suppressor gene, global genomic hypomethylation and covalent modifications of histone N-terminal tails which are protruding out from the nucleosome core. In sharp contrast with genetic modifications, epigenetic modifications are highly dynamic and reversible. The characterization of specific inhibitors directed against some key epigenetic players has opened a new and promising therapeutic avenue, the epigenetic therapy, since some inhibitors are already used in clinical trials.     

Galectins and cancer

The galectins are a family of proteins that are distributed widely in all living organisms. All of them share galactose-specificity. At present, 14 members of the family are characterized in mammals. The galectins have been implicated in many essential functions including development, differentiation, cell-cell adhesion, cell-matrix interaction, growth regulation, apoptosis, RNA splicing, and tumor metastasis. Although efforts have mostly focused on the possible function of galectins in tumor development and invasiveness, their precise role in this field is still debated. This review discusses the recent way in which the expression of galectins and galectin-binding sites may affect the behavior of a variety of human neoplastic tissues.     

Immunonutrition and cancer

The immune system is the body's primary defence against invading pathogens, non-self components and cancer cells. Inflammatory processes, including the release of pro-inflammatory cytokines and formation of reactive oxygen and nitrogen species, are an essential part of these processes. Although such actions are usually followed rapidly by anti-inflammatory effects, excessive production of pro-inflammatory cytokines, or their production in the wrong biological context may lead to situations of chronic inflammation. Whether such conditions arise as a result of exogenous chemicals, invading pathogens or disease processes, the long-term implications include an increased risk of cancer. A number of nutrients have the ability to modulate immune response and counter inflammatory processes. Zinc, epigallocatechin galate (EGCG), omega-3 polyunsaturated fatty acids and probiotics all act differently to modulate immune response, but all appear to have the potential to protect against cancer development and progression. We suggest that immunonutrition may provide a less invasive alternative to immunotherapy in protection against cancers associated with chronic inflammation.     

Autophagy and cancer

(Macro)autophagy is a cellular membrane trafficking process that serves to deliver cytoplasmic constituents to lysosomes for degradation. At basal levels, it is critical for maintaining cytoplasmic as well as genomic integrity and is therefore key to maintaining cellular homeostasis. Autophagy is also highly adaptable and can be modified to digest specific cargoes to bring about selective effects in response to numerous forms of intracellular and extracellular stress. It is not a surprise, therefore, that autophagy has a fundamental role in cancer and that perturbations in autophagy can contribute to malignant disease. We review here the roles of autophagy in various aspects of tumor suppression including the response of cells to nutrient and hypoxic stress, the control of programmed cell death, and the connection to tumor-associated immune responses.     

Bioelectronics and cancer

The appearance of oxygen on our globe induced profound changes in the nature of living systems which started to differentiate and build complex structures with complex functions. Oxidation was added to fermentation and unbridled proliferation was subjected to regulation. Fermentation demanded no structure, being the result of the action of a series of single molecules. Oxidation, with its electron flow, demanded structure and electronic mobility. To produce meaningful structures and complex functions the action of the single molecules had to be integrated. The question is: how could oxygen bring about these transformations? These changes are not limited to the distant past because in every division the cell has to revert, to some extent, to the undifferentiated, fermentative, proliferative state of ist earlier anaerobic period. After having completed its division, it has to find its way back to its oxidative resting state. If this road of return is deranged the cell has to go on dividing as it does in cancer. By elucidating the details of these processes we can hope to be able to control them. We can control only what we understand (Bernal). That oxygen can induce profound changes in cell life can be demonstrated even in the acute experiment. L. Pasteur showed that fermentation is inhibited by the admission of oxygen (“Pasteur Reaction”), and H. G. Crabtree demonstrated the opposite effect. The intimate relation of cancer and oxygen was made evident by H. Goldblatt and G. Cameron who provoked malignant transformation in their tissue culture by periodically limiting their oxygen supply. O. Warburg attributed the changes, induced by O₂, to a wealth of energy it produced. Undoubtedly, without a new and rich source of energy these changes could not have occurred. Energy made them possible, but energy offers no mechanism. The chemical mechanism underlying these transformations will be the main topic of this paper and it will be shown that charge transfer is one of the central biological reactions. A biologist trying to understand life without electronic mobility is comparable to a Martian trying to understand our civilization without knowing about electricity. This paper will chiefly be concerned with principles. The chemical methods employed will be discussed in a subsequent paper by Dr. L. Egyud.     

TGF-beta and cancer

TGF-beta signaling regulates tumorigenesis and in human cancer its signaling pathways are often modified during tumor progression. Prior to initiation and early during progression TGF-beta acts upon the epithelium as a tumor suppressor, however at later stages it is often a tumor promoter. Over the years, many studies have focused on the epithelial cell autonomous role for TGF-beta, however, TGF-beta is not strictly limited to this compartment in vivo. Recent studies addressing TGF-beta mediated stromal-epithelial interactions have significantly improved our understanding related to the regulation of cancer. In addition, stromal fibroblast cell autonomous effects have been observed in response to TGF-beta stimulation. According to the current literature and experimental evidence, TGF-beta is a potent ligand that regulates carcinoma initiation, progression and metastasis through a broad and complex spectrum of interdependent interactions.     

Caspases and cancer

Evasion of apoptosis is considered to be one of the hallmarks of human cancers. This cell death modality is executed by caspases and several upstream regulatory factors, which direct their proteolytic activity, have been defined as either tumor suppressors or oncogenes. Often these regulatory factors, in addition to being potent apoptosis inducers, function in cell survival or repair signaling pathways in response to cellular stress. Thus, loss of function in a distinct regulatory mechanism does not necessarily mean that tumor formation is due to apoptosis malfunction resulting from insufficient caspase activation. Although each caspase has been assigned a distinct role in apoptosis, some redundancy with respect to their regulatory functions and substrate recognition is evident. Jointly, these proteases could be considered to possess solid tumor suppressor function, but what is the evidence that deregulation of specific caspases per se induces inappropriate cell survival, leading to enhanced tumorigenic potential? This question will be addressed in this review, which covers basic molecular mechanisms derived from in vitro analyses and emphasizes new insights that have emerged from in vivo and clinical studies.     

microRNA与肿瘤

microRNA（miRNA）是近年来发现的一类长度为19—25个核苷酸的非编码小分子RNA。它主要通过与靶标基因3’UTR的完全或不完全配对,降解靶标基因mRNA或抑制其翻译,从而参与调控个体发育、细胞凋亡、增殖及分化等生命活动。实验证据表明,miRNA可通过调控其靶标基因参与的信号通路,影响肿瘤的发生和发展,发挥着类似于癌基因或抑癌基因的功能。miRNA的发现为肿瘤发病机制的研究提供了新的思路,为肿瘤诊断和治疗提供了新的策略。本综述主要介绍近年来miRNA与肿瘤发生发展相关性研究领域的进展。