Nat Rev Urol. 2018 May;15(5):321-333.

A stage-dependent link between metabolic syndrome components and incident prostate cancer

Jan Hammarsten1, Jan-Erik Damber1, Mohammad A. Haghsheno1, Dan Mellström2 and Ralph Peeker1

1 Department of Urology, University of Gothenburg, Sweden

2 Department of Geriatrics, University of Gothenburg, Sweden

 Correspondence to: J.H. jan.hammarsten@telia.com

 

Abstract

Metabolic syndrome is associated with increased cancer risk and progression at almost all sites, including the prostate in high-stage prostate cancer. However, several reports have described an inverse relationship between metabolic syndrome and its components and low-stage incident prostate cancer. Such anomalies hamper research efforts to fight cancer. Evidence suggests that metabolic syndrome and its components have two distinct effects in prostate cancer, concealing low-stage prostate cancer and promoting progression to high-stage incident, non-localized, and lethal prostate cancer. The concealment of prostate cancer by metabolic syndrome and its components may be related to bias mechanisms that reduce PSA levels and lead to a delayed diagnosis of low-stage prostate cancer, meaning that fewer men with metabolic syndrome are diagnosed with low-stage disease. The inverse link between metabolic syndrome and its components and low-stage incident prostate cancer might simply be the result of such bias and the shortcomings of the diagnostic procedure, rather than prostate cancer biology. The evidence summarized here supports the hypothesis that the link between metabolic syndrome and its components and incident prostate cancer is two-way and stage-dependent, a theory that requires further research.

 

 

Summary

In the 1990s, epidemiological studies demonstrated that metabolic syndrome and its aspects are linked to cancer at almost all sites (1,2), including the prostate gland (2-5). Based on these findings, the metabolic syndrome-cancer hypothesis was formulated. However, when it comes to prostate cancer, a series of reports were published in the 2000s, showing an inverse relationship between metabolic syndrome and its aspects and incident prostate cancer. This finding seemed to falsify the metabolic syndrome-cancer hypothesis, and this lack of coherence in cancer research seriously hampers efforts to fight cancer disorders. Therefore, it is crucial to find an explanation for this incoherence. Our research group recently addressed this challenge (6).

Formulation of a hypothesis

We formulated the hypothesis that these anomalous observations in prostate cancer research are explained by the fact that the diagnostic procedure in the 1990s was driven more by symptoms; therefore, more men with high-stage incident prostate cancer were diagnosed. In contrast, the diagnostic approach in the 2000s was more prostate-specific antigen (PSA)-driven, resulting in a different case mix, with an increased proportion of low-stage incident prostate cancer (6).

Test of the hypothesis

Our findings showed that the link between metabolic syndrome components and incident prostate cancer was negative in reports dominated by low-stage prostate cancer, and the link between metabolic syndrome components and incident prostate cancer was positive in reports dominated by high-stage prostate cancer (6).

Bias mechanisms

Our findings support the hypothesis that the inverse link between metabolic syndrome and its components and low-stage incident prostate cancer in the 2000s was related to a bias mechanism rather than prostate cancer biology. Inherent in this interpretation is that men with metabolic syndrome and its components have lower testosterone levels than men without these conditions (7-9). The testosterone level controls PSA production (10), and metabolic syndrome has been shown to have a lowering effect on serum PSA (11). In addition, men with metabolic syndrome are more obese and have larger plasma volumes and, therefore, greater dilution of serum PSA and lower PSA concentration (12). Thus, men with metabolic syndrome and its components have lower PSA levels than men without these disorders (11). Consequently, fewer men with metabolic syndrome and its components have a prostate cancer diagnosis than men without these conditions, as more men with metabolic syndrome will end up under the PSA threshold (>3.0 ng/ml) for prostate biopsy. In contrast, in high-stage, non-localized and lethal prostate cancer, a reduced androgen level has no influence on the prostate cancer diagnosis because of the high PSA levels in these manifestations of the disease. A minor reduction in the PSA level has no relevance for the prostate cancer diagnosis at these high PSA levels. Thus, the findings suggest that the negative link between metabolic syndrome and its components and incident prostate cancer in low-stage prostate cancer is related to a metabolic syndrome-associated bias mechanism rather than prostate cancer biology.

Restoration of the metabolic-cancer hypothesis

Consequently, the falsification of the metabolic syndrome–cancer hypothesis suggested by reports published during the 2000s can be rejected. The findings suggest a restoration of the metabolic syndrome-cancer hypothesis.

Our conclusion is that, if the negative relationship between metabolic syndrome and its aspects and incident prostate cancer can be confirmed to be a spurious observation resulting from a bias mechanism, this would pave the way for the metabolic syndrome-cancer hypothesis regarding the promotion of all cancer manifestations. This could lead to increased efforts to fight the metabolic aberrations of metabolic syndrome and its components. The basic approach for the purpose of cancer prevention and treatment in patients with metabolic syndrome and its aspects is to prevent risk factors. Inherent to this concept is the possibility that treating one or several risk factors might reduce the risk of being diagnosed with cancer and reduce the progress of an already established cancer. Metabolic syndrome and its components can be reduced by changes in lifestyle, including a reduction of chronic stress, smoking cessation, treatment of vitamin D deficiency, increased physical activity, and reduced carbohydrate consumption. The most convincing evidence of the effect of diet on metabolic syndrome and its components comes from studies involving decreased intake of carbohydrates and increased intake of saturated fats. Leading authorities in nutrition, endocrinology, and metabolism presented a critical review and concluded that carbohydrate restriction is the single most effective intervention to reduce all features of metabolic syndrome (13). Another review concluded that carbohydrate restriction is one of the few common interventions that target all features of metabolic syndrome (14). This conclusion was confirmed recently in an open label, non-randomized, control study by Hallberg et al. (15). A total of 262 adults with type 2 diabetes were subjected to carbohydrate restriction for 1 year. After 1 year, the following significant average changes were revealed: fasting insulin -43%, C-peptide -23%, HOMA-IR -55%, fasting glucose -22%, HbA1c -17%, triglycerides -24%, HDL-cholesterol +18%. The average body weight declined 13.8+0.71 kg and blood pressure improved. The control group, which consisted of 87 adults with recently diagnosed type 2 diabetes subjected to usual care, had no significant changes in biomarkers after 1 year. However, the real benefit of promoting healthier lifestyles for the purpose of altering the propensity to develop cancer remains to be clarified in intervention studies.

Implications for prostate cancer

Regarding prostate cancer, the most important conclusion was that our data suggest that the negative link between metabolic syndrome and its components and incident prostate cancer in the 2000s can be attributed to bias mechanisms that masked the positive link in reports based on PSA-driven diagnostics. Another conclusion was that prostate cancer could be considered to be a new component of metabolic syndrome, as metabolic syndrome and its aspects are positively related to high-stage, non-localized, and lethal prostate cancer. Still another conclusion was that men with high-stage, non-localized, and lethal prostate cancer are metabolically sicker than men with low-stage, localized, and non-lethal prostate cancer. In the clinical setting, our data indicate that the presence of metabolic syndrome and its components at diagnosis should alert the clinician to the possibility that the patient might be at risk of developing advanced prostate cancer. Another consequence in the clinical setting could be a reduction in the overtreatment of prostate cancer detected by PSA screening procedures because a low-risk group could be identified.

Implications for cancer manifestations in general

Regarding cancer manifestations in general, the most important conclusion was that our findings seem to restore the metabolic syndrome-cancer hypothesis. Metabolic syndrome was linked to high stage prostate cancer, as is the case with cancers at most other sites. If this is true, one could visualize the metabolic cancer tree as a hypothetical metaphor for the pathophysiology of cancer (Fig 1). Our findings suggest that lifestyle changes that alter the metabolic profile of the patient can be used for treatment and primary, secondary, and tertiary prevention of cancer. The most robust data for achieving this goal come from reports of the results of carbohydrate restriction. If our findings are confirmed, physicians should be aware of the effect that metabolic syndrome and its components have on cancer and be prepared to discuss this idea with their patients and suggest lifestyle changes. We need to convey this message to the community and to the medical profession for the purpose of curbing the growing global cancer epidemic.

 

The metabolic cancer tree

Fig 1 The metabolic cancer tree illustrates a hypothetical metaphor for the pathophysiology of cancer. At the root of the tree is the overconsumption of carbohydrates, which creates insulin resistance. Other lifestyle factors, such as chronic stress, smoking, vitamin D deficiency, and low physical activity, might also create insulin resistance. Insulin resistance and the increased insulin levels that accompany it are at the core of metabolic syndrome and its components. At the top of the tree are cancer manifestations, including prostate cancer, bladder cancer, colon cancer, and breast cancer, among others.

 

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