Mini-symposium: diagnostic molecular pathology
The pathogenesis of prostate cancer: from molecular to metabolic alterations

https://doi.org/10.1016/j.mpdhp.2008.03.001Get rights and content

Abstract

Prostate cancer (PCa) is a heterogeneous disease with regard to molecular alterations and clinical course. The investigation of genetic alterations associated with PCa pathogenesis is highly challenging. Genome-wide analyses and epidemiological studies have identified only a handful of candidate genes possibly associated with hereditary or sporadic PCa. Cancer cells often rely for survival on common biochemical pathways such as enhanced anaerobic glycolysis and lipogenesis. The lipogenic enzyme fatty acid synthase seems to play a crucial part in PCa by conferring growth and survival advantages to cancer cells. We summarize the current understanding of the molecular events in PCa, and highlight the importance of altered lipid metabolism in the development and progression of prostate malignancy.

Section snippets

Epidemiology

Among the male population of the USA, prostate cancer is the most prevalent non-cutaneous neoplasm (1 in 6 men will be diagnosed with PCa cancer during their lifetime) and a leading cause of cancer-related death, second only to lung and colon cancer.1 Its frequency varies widely, with the highest rates reported in Western countries, and the lowest rates in Asia.2 Multiple factors contribute to the high incidence and prevalence of PCa. Risk factors include age, family history and race, but also

Genetic mutations and epigenetic changes in prostate cancer

Analyses of polymorphic microsatellites have shown that multiple foci of cancer arise independently within the same prostate.9 An increasing number of studies prove that prostate cancer can be genetically classified into different subgroups, exemplifying the extensive phenotypic and molecular heterogeneity of this disease. Genetic profile analyses have detected only a few, potentially significant mutations in hereditary and sporadic prostate cancer.

Metabolic alterations in tumour initiation and in androgen-independent disease

Pioneering efforts on the characterization of tumour metabolism have revealed that cancer cells rely on anaerobic pathways to convert glucose to ATP, even in abundant oxygen.23 This phenomenon, known as the Warburg effect, occurs despite the fact that the anaerobic pathway is less efficient for energy supply than aerobic respiration.

Warburg claimed that the first phase of cancer genesis is irreversible injury to the respiratory chain. Due to the resulting defective aerobic energy production,

Conclusions

In this review, the authors suggested that interfering with lipid metabolism has detrimental effects on prostate tumour cell survival. Studies are under way to determine the precise mechanisms responsible for tumour initiation and maintenance by altered metabolic pathways.

From a broader perspective, the authors would like to underscore the necessity of more thorough investigations of the metabolic alterations in cancer, and speculate that combining metabolic profiling with genome-wide analyses

Acknowledgments

We thank members of Loda laboratory for fruitful discussions, particularly Emanuele Palesandolo, Carmen Priolo, Stephen Finn and Giorgia Zadra; Sonal Jhaveri-Schneider for critical review of the manuscript; Marleen Marino and Jane Hayward for graphic assistance.

This work was supported by the Gelb Center for genitourinary oncology and by grants from the NIH (Specialized Programs of Research Excellence 5P50CA90381, PO1 CA089021) and the Prostate Cancer Foundation (Massimo Loda). ML is a Novartis

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