Micronutrients and cancer prevention: are the RDAs adequate?

The involvement of certain micronutrients (vitamin C, vitamin E, beta-carotene, selenium) in the antioxidant defense system against free radical cell damage, and of vitamin A in the differentiation of epithelial cells, has raised the question whether intakes of these nutrients in excess of their recommended daily allowances should be recommended to the general public for cancer prevention. The considerations surrounding this question are discussed, and it is concluded that such measures are unjustified by present epidemiological and experimental evidence. Any such action should await the outcome of ongoing intervention trials.     

Stem cells: The root of prostate cancer?

The cancer stem cell (CSC) model states that tumors contain a reservoir of self-renewing cells that maintain the heterogeneous cell population of the tumor. These cells appear to be resistant to therapy and can therefore survive to repopulate the tumor during progression to therapy resistant disease. The biology of CSCs is still not definitive since it is difficult to isolate them from solid tumors and analyze their characteristics in vitro. Another challenge is to correlate these characteristics with tumor development and progression in vivo. Using the prostate CSC as a model, this review presents the CSC hypothesis, reviews the origin, identification and functions of prostate CSCs, and discusses the clinical implications and therapeutic challenges CSCs have for cancer therapy.     

Oxidative stress-related aging: A role for prostate cancer?

Prostate cancer has the highest prevalence of any non-cutaneous cancer in the human body and essentially all men with circulating androgens will develop microscopic prostate cancer if they live long enough. Aging, considered as an impairment of body functions over time, caused by the accumulation of molecular damage in DNA, proteins and lipids, is also characterized by an increase in intracellular oxidative stress due to the progressive decrease of the intracellular ROS scavenging. The aging damage may eventually appear in age-related health issues, which have a significant impact on the independence, general well-being and morbidity of the elderly. The association of aging with prostate cancer is undisputable as well as the association of aging with oxidative stress. Nevertheless, supportive evidence linking an increase in oxidative stress with prostate cancer is still scarce. This review is a comprehensive, literature-based analysis of the association of human prostate cancer with oxidative stress. The objective was to examine the involvement of reactive oxygen species in the mechanisms of prostatic carcinogenesis since the understanding of risk factors for prostate cancer has practical importance for public health, genetic and nutritional education, and chemoprevention.     

Diagnosing cancer in general practice: when is cancer suspected?

Of 10,278 encounters with patients recorded by 33 general practitioners in a defined Norwegian population during a two month period, 429 (4.2%) were classified as resulting in a follow up for suspected cancer. The patient''s fear of cancer was the most important indicator of suspicion of cancer among the doctors. Patients who consulted for digestive and gynaecological problems were most frequently suspected of having cancer. Comparing the pattern of suspicion of cancer with the incidence of cancer in the area showed a relative oversuspicion in young patients and women.     

Tissue transglutaminase, inflammation, and cancer: how intimate is the relationship?

Despite significant advances in surgery and biology, cancer remains a major health problem. It is now well accepted that metastasis and cancer cells’ acquired or inherent resistance to conventional therapies are major roadblocks to successful treatment. Chronic inflammation is an important driving force that provides a favorable platform for cancer’s progression and development and suggests a link between inflammation and metastatic transformation. However, how chronic inflammation contributes to metastatic cell transformation is not well understood. According to the current theory of cancer progression, a small subpopulation of cancer stem cells (CSCs) in tumors is responsible for their metastasis, resistance, and sustenance. Whether CSCs originate from normal stem cells or from dedifferentiation of terminally differentiated cells remains unknown. Recent evidence indicates that stem cells are not unique; malignant or nonmalignant cells can reprogram and de-differentiate to acquire a stemness phenotype. Thus, phenotypic plasticity may exist between stem cells and non-stem cells, and a dynamic equilibrium may exist between the two phenotypes. Moreover, this equilibrium may shift in one direction or another on the basis of contextual signals in the microenvironment that influence the interconversion between stem and non-stem cell compartments. Whether the inflammatory microenvironment influences this interconversion and shifts the dynamic equilibrium towards stem cell compartments remains unknown. We recently found that aberrant tissue transglutaminase (TG2) expression induces the mesenchymal transition (EMT) and stem cell characteristics in epithelial cells. This finding, in conjunction with the observation that inflammatory signals (e.g., TGFβ, TNFα, and NF-κB) which induce EMT, also induce TG2 expression, suggests a possible link between TG2, inflammation, and cancer progression. In this review, we summarize TG2-driven processes in inflammation and their implications in cancer progression.     

Fatty acid synthase: A metabolic oncogene in prostate cancer?

In 1920, Warburg suggested that tumors consistently rely on anaerobic pathways to convert glucose to ATP even in the presence of abundant oxygen [Warberg, 1956] despite the fact that it is less efficient for energy supply than aerobic glycolysis. The reasons for this remain obscure to date. More often than not, the microenvironment of solid tumors contains regions of poor oxygenation and high acidity. In this context hypoxia can act in an epigenetic fashion, inducing changes in gene expression and in metabolism for survival. It is reasonable to assume that only the tumor cells capable of developing an unusual tolerance to limiting oxygen availability and to the acidosis resulting from excessive lactate production, can survive. In addition to the striking changes that occur in glucose metabolism, studies in human cancer patients suggest that there is often also an increase in free fatty acid turnover, oxidation and clearance [Legaspi et al., 1987; Hyltander et al., 1991]. For instance, a lipid mobilizing factor produced by tumor cells appears to be responsible for the increase in whole body fatty acid oxidation [Russell and Tisdale, 2002]. Fatty acids synthesis in tumor tissues also occurs at very high rates, as first demonstrated more than half a century ago [Medes et al., 1953]. Importantly, (14)C glucose studies have shown that in tumor cells almost all fatty acids derive from de novo synthesis despite adequate nutritional supply [Sabine and Abraham, 1967; Ookhtens et al., 1984; Weiss et al., 1986]. In addition, tumors overexpressing fatty acid synthase (FAS), the enzyme responsible for de novo synthesis of fatty acids, display aggressive biologic behavior compared to those tumors with normal FAS levels, suggesting that FAS overexpression confers a selective growth advantage. Here, we will review the roles that FAS plays in important cellular processes such as apoptosis and proliferation. In addition, speculations on the putative role of FAS in the altered metabolic pathways of prostate cancer cells will be explored. Because of the frequent overexpression of this enzyme prostate cancer, FAS constitutes a therapeutic target in this disease.     

The cancer stem cell theory: is it correct?

The cancer stem cell hypothesis posits that tumor growth is driven by a rare subpopulation of cells, designated cancer stem cells (CSC). Studies supporting this theory are based in large part on xenotransplantation experiments wherein human cancer cells are grown in immunocompromised mice and only CSC, often constituting less than 1% of the malignancy, generate tumors. Herein, we show that all colonies derived from randomly chosen single cells in mouse lung and breast cancer cell lines form tumors following allografting histocompatible mice. Our study suggests that the majority of malignant cells rather than CSC can sustain tumors and that the cancer stem cell theory must be reevaluated.