Aberrations in circulating ceramide levels are associated with poor clinical outcomes across localised and metastatic prostate cancer

Lin, Hui-Ming; Huynh, Kevin; Kohli, Manish; Tan, Winston; Azad, Arun; Yeung, Nicole; Mahon, Kate; Mak, Blossom; Sutherland, Peter; Shepherd, Andrew; Mellett, Natalie A.; Docanto, Maria; Giles, Corey; Centenera, Margaret M.; Butler, Lisa M.; Meikle, Peter J.; Horvath, Lisa G.

doi:10.1038/s41391-021-00338-z

Cited by 17 publications

(52 citation statements)

References 36 publications

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“…The cohorts and study schema are summarised in Figure 1 . Cohort 1 has been described previously with regards to their lipidomic analysis [ 7 ] and consists of 146 men who received docetaxel as a first line therapy for mCRPC. Cohort 2 is an independent cohort of 139 men who received first line or subsequent life-prolonging therapy for mCRPC.…”

Section: Resultsmentioning

confidence: 99%

“…Obesity is associated with higher rates of relapse and prostate-cancer-specific mortality [ 6 ]. Circulating lipid profiles that are rich in sphingolipids, especially ceramides, are associated with higher rates of metastatic relapse in prostate cancer, shorter time to androgen-deprivation therapy failure in metastatic hormone-sensitive prostate cancer (mHSPC), and shorter overall survival (OS) in mCRPC [ 7 , 8 ]. Furthermore, a poor prognostic three-lipid signature (3LS) in the plasma of patients with mCRPC was validated in two independent cohorts [ 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

“…Circulating lipid profiles that are rich in sphingolipids, especially ceramides, are associated with higher rates of metastatic relapse in prostate cancer, shorter time to androgen-deprivation therapy failure in metastatic hormone-sensitive prostate cancer (mHSPC), and shorter overall survival (OS) in mCRPC [ 7 , 8 ]. Furthermore, a poor prognostic three-lipid signature (3LS) in the plasma of patients with mCRPC was validated in two independent cohorts [ 7 , 8 ]. It is important to note that the association of circulating ceramides with prognosis in both castration (mCRPC) and non-castration settings (localised and mHSPC) indicates that the prognostic association of these lipids was independent of the metabolic effects of ADT.…”

Section: Introductionmentioning

confidence: 99%

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Relationship between Circulating Lipids and Cytokines in Metastatic Castration-Resistant Prostate Cancer

Lin

Yeung

Hastings

et al. 2021

Cancers

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Circulating lipids or cytokines are associated with prognosis in metastatic castration-resistant prostate cancer (mCRPC). This study aimed to understand the interactions between lipid metabolism and immune response in mCRPC by investigating the relationship between the plasma lipidome and cytokines. Plasma samples from two independent cohorts of men with mCRPC (n = 146, 139) having life-prolonging treatments were subjected to lipidomic and cytokine profiling (290, 763 lipids; 40 cytokines). Higher baseline levels of sphingolipids, including ceramides, were consistently associated with shorter overall survival in both cohorts, whereas the associations of cytokines with overall survival were inconsistent. Increasing levels of IL6, IL8, CXCL16, MPIF1, and YKL40 correlated with increasing levels of ceramide in both cohorts. Men with a poor prognostic 3-lipid signature at baseline had a shorter time to radiographic progression (poorer treatment response) if their lipid profile at progression was similar to that at baseline, or their cytokine profile at progression differed to that at baseline. In conclusion, baseline levels of circulating lipids were more consistent as prognostic biomarkers than cytokines. The correlation between circulating ceramides and cytokines suggests the regulation of immune responses by ceramides. The association of treatment response with the change in lipid profiles warrants further research into metabolic interventions.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Relationship between Circulating Lipids and Cytokines in Metastatic Castration-Resistant Prostate Cancer

Lin

Yeung

Hastings

et al. 2021

Cancers

Self Cite

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“…Patients with elevated ceramide levels were more likely to have metastatic relapse, therapeutic failure (ADT/docetaxel), and shorter overall survival. The authors also validated a previously published prognostic 3-lipid signature with potential clinical traslation ( 152 ). Both ceramide and C1P are activators of PLA2, an enzyme that releases AA for subsequent conversion to prostaglandins, molecules involved in inflammation, immunity, and tumor growth modulation (see below).…”

Section: The Role Of Lipids As Signaling Mediators In Pcamentioning

confidence: 95%

“…The authors derived a prognostic three-lipid signature (ceramide d18:1/24:1, sphingomyelin d18:2/16:0, phosphatidylcholine 16:0/16:0) as independent prognostic factor (197). More recently, the same group detected elevated circulating ceramide species in association with poorer clinical outcomes across the PCa progression and validated the three-lipid prognostic signature in an independent cohort (152). These studies not only identified an easily detectable prognostic biomarker but also highlighted the crucial role of sphingolipids in PCa progression.…”

Section: Application Of Lipidomics and Mass-spectrometry Imaging In Pca Researchmentioning

confidence: 95%

Prostate Cancer Progression: as a Matter of Fats

2021

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Advanced prostate cancer (PCa) represents the fifth cause of cancer death worldwide. Although survival has improved with second-generation androgen signaling and Parp inhibitors, the benefits are not long-lasting, and new therapeutic approaches are sorely needed. Lipids and their metabolism have recently reached the spotlight with accumulating evidence for their role as promoters of PCa development, progression, and metastasis. As a result, interest in targeting enzymes/transporters involved in lipid metabolism is rapidly growing. Moreover, the use of lipogenic signatures to predict prognosis and resistance to therapy has been recently explored with promising results. Despite the well-known association between obesity with PCa lethality, the underlying mechanistic role of diet/obesity-derived metabolites has only lately been unveiled. Furthermore, the role of lipids as energy source, building blocks, and signaling molecules in cancer cells has now been revisited and expanded in the context of the tumor microenvironment (TME), which is heavily influenced by the external environment and nutrient availability. Here, we describe how lipids, their enzymes, transporters, and modulators can promote PCa development and progression, and we emphasize the role of lipids in shaping TME. In a therapeutic perspective, we describe the ongoing efforts in targeting lipogenic hubs. Finally, we highlight studies supporting dietary modulation in the adjuvant setting with the purpose of achieving greater efficacy of the standard of care and of synthetic lethality. PCa progression is “a matter of fats”, and the more we understand about the role of lipids as key players in this process, the better we can develop approaches to counteract their tumor promoter activity while preserving their beneficial properties.

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Resistance to prostate cancer treatments

Krause

2022

IUBMB Life

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A review of the current treatment options for prostate cancer and the formation of resistance to these regimens has been compiled including primary, acquired, and cross-resistance. The diversification of the pathways involved and the escape routes the tumor is utilizing have been addressed. Whereas early stages of tumor can be cured, there is no treatment available after a point of no return has been reached, leaving palliative treatment as the only option. The major reasons for this outcome are the heterogeneity of tumors, both inter-and intra-individually and the nearly endless number of escape routes, which the tumor can select to overcome the effects of treatment. This means that more focus should be applied to the individualization of both diagnosis and therapy of prostate cancer. In addition to current treatment options, novel drugs and ongoing clinical trials have been addressed in this review.

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Aberrations in circulating ceramide levels are associated with poor clinical outcomes across localised and metastatic prostate cancer

Cited by 17 publications

References 36 publications

Relationship between Circulating Lipids and Cytokines in Metastatic Castration-Resistant Prostate Cancer

Relationship between Circulating Lipids and Cytokines in Metastatic Castration-Resistant Prostate Cancer

Prostate Cancer Progression: as a Matter of Fats

Resistance to prostate cancer treatments

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