Metastasis is the hallmark of cancer that is responsible for the greatest number of cancer-related deaths. Yet, it remains poorly understood. The continuous evolution of cancer biology research and the emergence of new paradigms in the study of metastasis have revealed some of the molecular underpinnings of this dissemination process. The invading tumor cell, on its way to the target site, interacts with other proteins and cells. Recognition of these interactions improved the understanding of some of the biological principles of the metastatic cell that govern its mobility and plasticity. Communication with the tumor microenvironment allows invading cancer cells to overcome stromal challenges, settle, and colonize. These characteristics of cancer cells are driven by genetic and epigenetic modifications within the tumor cell itself and its microenvironment. Establishing the biological mechanisms of the metastatic process is crucial in finding open therapeutic windows for successful interventions. In this review, the authors explore the recent advancements in the field of metastasis and highlight the latest insights that contribute to shaping this hallmark of cancer.

/pdf/molecular-principles-of-metastasis-a-hallmark-of-cancer-2owibp00tb.pdf

Molecular principles of metastasis: a hallmark of cancer revisited

Melatonin is a tryptophan-derived molecule with pleiotropic activities. It is present in almost all or all organisms. Its synthetic pathway depends on the species in which it is measured. For example, the tryptophan to melatonin pathway differs in plants and animals. It is speculated that the melatonin synthetic machinery in eukaryotes was inherited from bacteria as a result of endosymbiosis. However, melatonin's synthetic mechanisms in microorganisms are currently unknown. Melatonin metabolism is highly complex with these enzymatic processes having evolved from cytochrome C. In addition to its enzymatic degradation, melatonin is metabolized via pseudoenzymatic and free radical interactive processes. The metabolic products of these processes overlap and it is often difficult to determine which process is dominant. However, under oxidative stress, the free radical interactive pathway may be featured over the others. Because of the complexity of the melatonin degradative processes, it is expected that additional novel melatonin metabolites will be identified in future investigations. The original and primary function of melatonin in early life forms such as in unicellular organisms was as a free radical scavenger and antioxidant. During evolution, melatonin was selected as a signaling molecule to transduce the environmental photoperiodic information into an endocrine message in multicellular organisms and for other purposes as well. As an antioxidant, melatonin exhibits several unique features which differ from the classic antioxidants. These include its cascade reaction with free radicals and its capacity to be induced under moderate oxidative stress. These features make melatonin a potent endogenously-occurring antioxidant that protects organisms from catastrophic oxidative stress.

https://www.mdpi.com/1420-3049/20/10/18886/pdf

Melatonin as a Potent and Inducible Endogenous Antioxidant: Synthesis and Metabolism.

Association between light at night, melatonin secretion, sleep deprivation, and the internal clock: Health impacts and mechanisms of circadian disruption.

Textbook of Cancer Epidemiology

The circadian clock is a complex cellular mechanism that, through the control of diverse metabolic and gene expression pathways, governs a large array of cyclic physiological processes. Epidemiological and clinical data reveal a connection between the disruption of circadian rhythms and cancer that is supported by recent preclinical data. In addition, results from animal models and molecular studies underscore emerging links between cancer metabolism and the circadian clock. This has implications for therapeutic approaches, and we discuss the possible design of chronopharmacological strategies.

/pdf/the-emerging-link-between-cancer-metabolism-and-circadian-2kqkx403fn.pdf

The Emerging Link between Cancer, Metabolism and Circadian Rhythms

Night shift work has been classified as a probable human carcinogen based on experimental studies and limited human evidence on breast cancer. Evidence on other common cancers, such as prostate cancer, is scarce. Chronotype is an individual characteristic that may relate to night work adaptation. We evaluated night shift work with relation to prostate cancer, taking into account chronotype and disease severity in a population based case-control study in Spain. We included 1,095 prostate cancer cases and 1,388 randomly selected population controls. We collected detailed information on shift schedules (permanent vs. rotating, time schedules, duration, frequency), using lifetime occupational history. Sociodemographic and lifestyle factors were assessed by face-to-face interviews and chronotype through a validated questionnaire. We used unconditional logistic regression analysis adjusting for potential confounders. Subjects who had worked at least for one year in night shift work had a slightly higher prostate cancer risk [Odds Ratio (OR) 1.14; 95%CI 0.94, 1.37] compared with never night workers; this risk increased with longer duration of exposure (≥28 years: OR 1.37; 95%CI 1.05, 1.81; p-trend = 0.047). Risks were more pronounced for high risk tumors [D'Amico classification, Relative Risk Ratio (RRR) 1.40; 95%CI 1.05, 1.86], particularly among subjects with longer duration of exposure (≥28 years: RRR 1.63; 95%CI 1.08, 2.45; p-trend = 0.027). Overall risk was higher among subjects with an evening chronotype, but also increased in morning chronotypes after long-term night work. In this large population based study, we found an association between night shift work and prostate cancer particularly for tumors with worse prognosis.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ijc.29400

Night shift work, chronotype and prostate cancer risk in the MCC‐Spain case‐control study

Night shift work has been associated with breast and prostate cancer. Recent studies on breast cancer indicate that risk is highest in women with current night-shift work and decreases with time since last night-shift work. We re-analysed data from the MCC-Spain population based case-control study to evaluate whether the attenuation shown for breast cancer by time since last exposure is also observed in prostate cancer. Incident histologically confirmed prostate cancer cases (n=1093) aged 27-85 were recruited in 11 hospitals in 7 Spanish regions 2008-2013 and were matched to a random sample of general population controls (n=1387). We recorded detailed information on shift work for all jobs and on lifestyle and sociodemographic factors. Subjects with current or recent night shift work (0-2 years) had an Odds Ratio of 1.25 (95%CI 0.86,1.80) compared to never night shift workers. A similar risk was observed for night shift workers who interrupted such an exposure less than 20 years ago (OR=1.23, 0.95,1.60). At 20 years since last exposure, there was no increased risk (OR=1.02, 0.8-1.3, p-value for trend=0.08). The pattern was similar when adjusting also for cumulative duration of night shift work. We describe a pattern of time-related decrease in prostate cancer risk following night shift work with a nearly null association 20 years after last exposure that has also been observed for breast cancer. This pattern may help understand mechanisms of disease and may also explain differences between findings of epidemiological studies. This article is protected by copyright. All rights reserved.

Prostate cancer risk decreases following cessation of night shift work.

Adherence to guideline recommendations in the management of upper tract urothelial carcinoma: an analysis of the CROES–UTUC registry

BACKGROUND
Current pathways in early diagnosis of prostate cancer (PCa) can lead to unnecessary biopsy procedures. Here, we used telomere analysis to develop and evaluate ProsTAV®, a risk model for significant PCa (Gleason score >6), with the objective of improving the PCa diagnosis pathway.


METHODS
This retrospective, multicentric study analyzed telomeres from patients with serum PSA 3-10 ng/mL. High-throughput quantitative fluorescence in-situ hybridization was used to evaluate telomere-associated variables (TAVs) in peripheral blood mononucleated cells. ProsTAV® was developed by multivariate logistics regression based on three clinical variables and six TAVs. The predictive capacity and accuracy of ProsTAV® were summarized by receiver operating characteristic (ROC) curves and its clinical benefit with decision curves analysis.


RESULTS
Telomeres from 1043 patients were analyzed. The median age of the patients was 63 years, with a median PSA of 5.2 ng/mL and a percentage of significant PCa of 23.9%. A total of 874 patients were selected for model training and 169 patients for model validation. The area under the ROC curve of ProsTAV® was 0.71 (95% confidence interval [CI], 0.62-0.79), with a sensitivity of 0.90 (95% CI, 0.88-1.0) and specificity of 0.33 (95% CI, 0.24-0.40). The positive predictive value was 0.29 (95% CI, 0.21-0.37) and the negative predictive value was 0.91 (95% CI, 0.83-0.99). ProsTAV® would make it possible to avoid 33% of biopsies.


CONCLUSIONS
ProsTAV®, a predictive model based on telomere analysis through TAV, could be used to increase the prediction capacity of significant PCa in patients with PSA between 3 and 10 ng/mL.

Javier Burgos

Papers

Night shift work, chronotype and prostate cancer risk in the MCC‐Spain case‐control study

Prostate cancer risk decreases following cessation of night shift work.

Adherence to guideline recommendations in the management of upper tract urothelial carcinoma: an analysis of the CROES–UTUC registry

ProsTAV, a novel blood-based test for biopsy decision management in significant prostate cancer.