Equine Melanocytic Tumors

Phillips, Jeffrey; Lembcke, Luis M.

doi:10.1016/j.cveq.2013.08.008

Cited by 52 publications

(63 citation statements)

References 49 publications

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“…Interestingly, genome analysis of thoroughbred horses revealed a positive selection for ACSS1 locus (50), and a polymorphism in ACSS1 was associated with elite racecourse performance of horses (51). These observations in the context of our data may explain why melanoma is more commonly seen in horses than any other domesticated animals (52,53). However, we show that depletion of ACSS1 or ACSS2 reduced the growth of melanoma xenografts.…”

Section: Discussionmentioning

confidence: 45%

Glucose-independent Acetate Metabolism Promotes Melanoma Cell Survival and Tumor Growth

Lakhter

Hamilton

Konger

et al. 2016

Journal of Biological Chemistry

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Tumors rely on multiple nutrients to meet cellular bioenergetics and macromolecular synthesis demands of rapidly dividing cells. Although the role of glucose and glutamine in cancer metabolism is well understood, the relative contribution of acetate metabolism remains to be clarified. We show that glutamine supplementation is not sufficient to prevent loss of cell viability in a subset of glucose-deprived melanoma cells, but synergizes with acetate to support cell survival. Glucose-deprived melanoma cells depend on both oxidative phosphorylation and acetate metabolism for cell survival. Acetate supplementation significantly contributed to maintenance of ATP levels in glucose-starved cells. Unlike acetate, short chain fatty acids such as butyrate and propionate failed to prevent loss of cell viability from glucose deprivation. In vivo studies revealed that in addition to nucleo-cytoplasmic acetate assimilating enzyme ACSS2, mitochondrial ACSS1 was critical for melanoma tumor growth in mice. Our data indicate that acetate metabolism may be a potential therapeutic target for BRAF mutant melanoma.Malignant cells undergo metabolic reprograming to fuel proliferation in a nutrient-limited environment. Tumor cells metabolize glucose in the presence of oxygen, a process known as the Warburg effect or aerobic glycolysis (1). The Warburg effect is generally considered as a metabolic hallmark of cancer (2), yet therapeutic targeting of underlying pathways has remained challenging. For example, BRAF inhibitors are the first line therapy for treatment of patients with mutant BRAFdriven melanoma (3). However, rapid development of resistance to these inhibitors involves reduction in glucose uptake and glycolysis (4,5). Recent studies demonstrated that tumor cells are dependent on glutamine metabolism to support cell proliferation (6). Glutamine metabolism enables maintenance of tricarboxylic acid (TCA) 2 cycle intermediates and plays a critical role in suppressing oxidative stress by supplying antioxidants. Although glutamine can synergize with glucose metabolism to support tumor cell proliferation, metabolic tracing studies in glucose-deprived cells revealed that an unknown source of carbon cooperated with glutamine in maintaining TCA cycle intermediates (7). Collectively, these studies suggest that malignant cells rapidly adapt to nutrient limitation by resetting their metabolism to maintain cell proliferation, thus hampering effective treatments.Similar to DNA synthesis, energy production and lipid synthesis are crucial biochemical processes in rapidly dividing cancer cells. Acetyl-CoA, a mitochondrial metabolite responsible for the TCA cycle and energy production is also the primary substrate for lipid synthesis. ATP citrate lyase (ACLY) plays a central role in mobilizing acetyl-CoA from the mitochondria to the cytoplasm. ACLY overexpression is frequently observed in tumors and its inhibition reduces tumor growth (8). Although BRAF inhibitor resistant melanoma shows reduced glucose uptake (4, 5), as opposed to the Warburg e...

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Section: Discussionmentioning

confidence: 45%

Glucose-independent Acetate Metabolism Promotes Melanoma Cell Survival and Tumor Growth

Lakhter

Hamilton

Konger

et al. 2016

Journal of Biological Chemistry

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“…The disease was recently reviewed (Metcalfe et al 2013, Moore et al 2013, Phillips and Lembcke 2013 and the term equine malignant melanoma (EMM) was proposed by Moore and colleagues (2013) to describe the common melanocytic disease occurring in horses, considering the malignant potential of this tumour during its course of disease. This review describes the aetiological basis of EMM, the genetic influence in its development, diagnosis, and the current therapeutic approaches.…”

Section: Introductionmentioning

confidence: 99%

Aetiology, clinical presentation and current treatment options of equine malignant melanoma – a review of the literature

Cavalleri¹,

Mählmann²,

Steinig³

et al. 2014

PHK

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Summary: This review aims at giving an overview of the aetiology, genetic basis and clinical signs of equine malignant melanoma (EMM), the diagnostic work-up and the current treatment options. The established association between certain genetic features and melanoma formation in horses is reviewed. Typically, grey horses are affected with EMM. Typical predilection sites are the ventral tail, perianal region, eyelids, lips, parotid, or guttural pouches. Tumours usually grow slowly, but frequently metastasize eventually. Chemotherapy with cisplatin, 5-Fluorouracil and cimetidine are reviewed. Surgical excision of solitary small tumours can be successful, but has no systemic therapeutic effect and cannot prevent tumour recurrence. In conclusion, therapeutic options are still limited and conventional therapy is hardly curative. Current research focuses on immune modifying therapies using either tumour antigens for therapeutic vaccination or antitumoural interleukins. The most promising therapeutic approach currently under investigation is gene therapy using a xenogenic DNA vaccine coding for tumour associated antigens such as tyrosinase and gene therapy using interleukin-12 and -18.

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“…The majority of therapies to date have had limited success in clinical trials. The most successful immunological treatment for EMM seems to be the xenogeneic DNA vaccination with human tyrosinase DNA (Phillips and Lembcke 2013). However, detailed results on the clinical off-label use of this vaccine have not yet been published.…”

Section: Future Outlook On Immune Therapy In Emmmentioning

confidence: 99%

“…The immunogenicity of melanoma antigens has been shown in several species (Speiser et al 2003, Gyorffy et al 2005, Wolchok et al 2007, Yuan et al 2009, Manley et al 2011 and can be presumed for equine melanoma as well due to the antitumoral response seen after immune modifying therapies in EMM-bearing horses (Jeglum 1997, Heinzerling et al 2001, Finocchiaro et al 2009, Müller et al 2011, Phillips and Lembcke 2013. Tumor-associated antibodies (TAA) are a central part in triggering this antitumoral response.…”

Section: Adaptive Immune Mechanismsmentioning

confidence: 99%

“…This vaccine was able to induce specific antibodies and a cellular immune response in clinically healthy horses . The clinical off-label use of this vaccine has resulted in a favourable outcome in several horses making the therapeutical value in the therapy of EMM promising (Phillips and Lembcke 2013). However, using a different DNA vector, xenogeneic DNA vaccination of melanoma-bearing horses using human tyrosinase DNA or human gp100 DNA did not show a beneficial advantage in comparison to interleukin 12 and 18 DNA therapy alone (Mählmann et al 2015).…”

Section: Blockage Of Host Moleculesmentioning

confidence: 99%

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Prospect for immunological therapies of the equine malignant melanoma

Cavalleri¹,

Mählmann²,

Schuberth³

et al. 2015

PHK

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Summary: Although equine melanocytic neoplasms occur frequently, at least in grey horses, their existence is neglected frequently, despite their potentially severe clinical consequences. Immune-based therapies have been investigated in human metastatic melanoma and offer encouraging results. Researchers have recently begun to explore the immunological approach in equine malignant melanoma (EMM) with some success. Therefore, this review aims at giving a short overview of the nature of EMM and providing insight into the immunological basis of melanocytic neoplasms in general. Equine malignant melanoma is a true neoplasm with a genetic basis. Initially they show a slow invasive growth, but they have the potential to metastasize. EMM and human malignant melanomas share various common histopathologic features. For the immune system eradication of the tumor is a challenge. Although solid tumors are often infiltrated with immune cells, they usually do not induce a significant tumor remission. The antitumoral immune response depends on factors of the innate immune system interacting in a coordinated fashion with the adaptive immune system. Antigen-presenting cells, neutrophilic granulocytes, and lymphoid cells may elicit antitumoral effects. This innate response precedes a downstream antigen-specific response. In the tumor microenvironment of solid tumors immune suppressive factors can induce immune escape mechanisms of the tumors. Immunological therapies of EMM include blockage of histamine 2 receptors on melanoma cells and lymphocytes, cancer vaccines and gene therapeutic approaches. This article focuses on the immunological therapeutic approach of EMM and gives an outlook on future implications.

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Equine Melanocytic Tumors

Cited by 52 publications

References 49 publications

Glucose-independent Acetate Metabolism Promotes Melanoma Cell Survival and Tumor Growth

Glucose-independent Acetate Metabolism Promotes Melanoma Cell Survival and Tumor Growth

Aetiology, clinical presentation and current treatment options of equine malignant melanoma – a review of the literature

Prospect for immunological therapies of the equine malignant melanoma

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