Autophagy and apoptosis: rivals or mates?

Autophagy, a cellular process of "self-eating" by which intracellular components are degraded within the lysosome, is an evolutionarily conserved response to various stresses. Autophagy is associated with numerous patho-physiological conditions, and dysregulation of autophagy contributes to the pathogenesis of a variety of human diseases including cancer. Depending on context, activation of autophagy may promote either cell survival or death, two major events that determine pathological process of many illnesses. Importantly, the activity of autophagy is often associated with apoptosis, another critical cellular process determining cellular fate. A better understanding of biology of autophagy and its implication in human health and disorder, as well as the relationship between autophagy and apoptosis, has the potential of facilitating the development of autophagy -based therapeutic interventions for human diseases such as cancer.     

Caspase-independent cell death?

Many cells die with apoptotic morphology and with documented activation of an effector caspase, but there are also many exceptions. Cells frequently display activation of other proteases, including granzymes, lysosomal cathepsins, matrix metalloproteinases, and proteasomal proteases, and others display morphologies that are not fully consistent with classical apoptosis. In some experimental situations, evidence of caspase-dependent death is indirect, demonstrating that the cell can activate caspases rather than that it does. In other situations, such as involution of mammary or prostate tissue, many cells display autophagic or other morphology different from apoptosis, and there is considerable evidence for the activation of a lysosomal system. Prior to total collapse and necrosis, cells that are in trouble can activate numerous physiological pathways toward self-destruction. Intrinsic or extrinsic routes to effector caspase activation are frequently the most rapid and efficient. If neither of these routes is immediately available, owing to mutation, genetic manipulation, inhibitor, or the biology of the cell, other routes may be followed, leading to variant forms of cell death that may display one or more characteristics of apoptosis. Experimental and therapeutic procedures must account for this possibility.     

The Benefit of the Neutropenic Diet: Fact or Fiction?

There really should not be a debate about the use of neutropenic diet for cancer patients. Its usefulness has never been scientifically proven. However, neutropenic diets remain in place in many institutions even though their usefulness is controversial. Neutropenic diets were once thought to be important in protecting patients from having to succumb to infection from neutropenia while undergoing chemotherapy. Although food may contain harmful organisms and research has shown that bacterial translocation is possible, recent studies have been unable to obtain significant differences between placebo and intervention groups. The dietetic challenges neutropenic patients struggle with include decreased quality of life, malnutrition, gastrointestinal side effects, food aversion, and impaired cell-mediated immunity from vitamin deficiency. Unanswered questions in regard to the neutropenic diet include the following: (a) which food should be included; (b) which food preparation techniques improve patient compliance; (c) which patient populations benefit most; and (d) when should such a diet be initiated. Without scientific evidence, the best advice for neutropenic patients is to follow food safety guidelines as indicated by government entities.     

Involvement of polyamines in apoptosis. Facts and controversies: effectors or protectors?

The natural polyamines (putrescine, spermidine and spermine) are ubiquitous low-molecular aliphatic amines that play multifunctional roles in cell growth and differentiation. Recently, evidence has merging that polyamines are actively involved in cell death. Changes in polyamine homeostasis have been reported during cell death of nerve cells, in programmed cell death of embryonic cells and in various in vitro models of apoptosis. Polyamines and many of their structural analogs exert cytotoxic effects in vitro as well in vivo. Furthermore, polyamine analogs and inhibitors of the polyamine anabolic/catabolic pathways modulate processes of cell death in a cell-type specific way. Much ambiguity exists in the working mechanisms by which polyamines mediate apoptosis since they have been shown to act as promoting, modulating or protective agents in apoptosis. Nevertheless, from the studies reviewed here it can be concluded that polyamines are critically involved in cellular survival which makes them suitable targets for therapeutic intervention that is specifically directed to cell death pathways.     

Radiation-induced cell death and dendritic cells: potential for cancer immunotherapy?

Dendritic cells are key orchestrators of the immune system. There is considerable interest in their use for treating cancer. Whether they initiate an effective cytotoxic response against antigen-bearing cells, or produce tolerance, depends on the context in which those antigens are presented. Ionising radiation, and the cell death it causes, has several properties that may facilitate such an effective response. A range of in-vitro and in-vivo data supports this, although potential problems exist that may require concurrent strategies.     

Tumor-mediated apoptosis of cancer-specific T lymphocytes--reversing the "kiss of death"?

Recent studies have provided evidence that some cancers can aberrantly express molecules capable of inducing apoptosis of tumor-reactive lymphocytes. Several other potential tumor escape mechanisms that can block the cytotoxic pathways activated by killer T cells have also been proposed.     

The mammary stem cell conundrum: is it unipotent or multipotent?

Exploring the normal biology and regulation of stem cells has the promise to yield insights into the etiological roots and survival of breast cancer cells. Many studies have supported the existence of a multipotent mammary stem cell that regenerates all aspects of glandular development. However, Van Keymeulen and colleagues (2011) illustrated the presence of lineage-restricted unipotent stem cells that self-renew and collaborate in postnatal mammary development, whereas multipotent stem cells were found only during embryonic mammogenesis. This prompts a re-evaluation of currently accepted mammary stem cell dynamics and conceivably its impact on the evolution of different breast cancer subtypes.     

The university and the needs of the society: what professional models?

An overview of the complex Italian situation and the consequences of the European integration, which puts an emphasis on the role of research and education involving the universities and the specific faculties, is given. Attention is then focused on the characteristics of the evolution of the medical activity and health services as for prevention, health education, more extensive knowledge and the need for continuing education. Different problems are tackled and pertinent suggestions are offered. The cultural and professional perspectives of the doctor should be considered within a new psychosocial approach to the illness, super- and hyper-specialization, collaboration and skills in non traditional fields. Medical education should be based on tutorial teaching and student-centered rather than on the traditional teacher centered-academic teaching. For better health care medical education and training should be updated with respect to the doctor-patient relationship as well as to the technological advances and team-work in medicine. The ethical aspects of the medical profession should be evidenced to be able to tackle the involved problems. The main features of the doctor of the future are the need and the difficulty of updating and life-long learning.     

Cancers of the colon and rectum: identical or fraternal twins?

Colorectal cancer represents a major cause of cancer morbidity and mortality, with approximately 1.2 million cases and 600,000 deaths worldwide each year. Because of the anatomic continuity of the colon into the rectum, cancers affecting these organs have historically been considered equivalent. In this Prospective, we discuss the clinical and experimental data suggesting that colon cancer and rectal cancer are highly related, but distinct, diseases. Reconsidering the relationship between these cancers has implications for the development of new therapeutic paradigms.     

The limitless role of p53 in cell cycle machinery: good news or bad news?

The p53 tumor suppressor gene acts as a great protagonist in deciding how cells undergo either cell cycle arrest or apoptosis after experiencing various stress signals, including DNA damage, hypoxia, oncogene activation, and hyperproliferation. Research on p53 is in steady expansion, as evidenced by the continual flood of papers claiming novel mutations, gain or loss of p53 functions, and gene interactions. The latest study carried out by Spurgers of Texas University and his Colleagues (J Biol Chem 2006; 281:25134-42) emphasizes the strong impact of p53 in the complicated machinery that regulates cell cycle progression. In this paper, microarray data and well-evaluated statistical procedures on PC3 and LNCaP prostate carcinoma cells, open new perspectives in p53 mechanisms and bring the simultaneous identification of novel p53-repressed cell cycle genes, hopefully providing significant improvements in the study of DNA damage response, multistep carcinogenesis, and treatment rationales and outcomes.