Lactate as Key Metabolite in Prostate Cancer Progression: What Are the Clinical Implications?

Abstract

Advanced prostate cancer represents the fifth leading cause of cancer death in men worldwide. Although androgen-receptor signaling is the major driver of the disease, evidence is accumulating that disease progression is supported by substantial metabolic changes. Alterations in de novo lipogenesis and fatty acid catabolism are consistently reported during prostate cancer development and progression in association with androgen-receptor signaling. Therefore, the term "lipogenic phenotype" is frequently used to describe the complex metabolic rewiring that occurs in prostate cancer. However, a new scenario has emerged in which lactate may play a major role. Alterations in oncogenes/tumor suppressors, androgen signaling, hypoxic conditions, and cells in the tumor microenvironment can promote aerobic glycolysis in prostate cancer cells and the release of lactate in the tumor microenvironment, favoring immune evasion and metastasis. As prostate cancer is composed of metabolically heterogenous cells, glycolytic prostate cancer cells or cancer-associated fibroblasts can also secrete lactate and create "symbiotic" interactions with oxidative prostate cancer cells via lactate shuttling to sustain disease progression. Here, we discuss the multifaceted role of lactate in prostate cancer progression, taking into account the influence of the systemic metabolic and gut microbiota. We call special attention to the clinical opportunities of imaging lactate accumulation for patient stratification and targeting lactate metabolism.

Keywords: biomarkers; lactate; metabolic imaging; monocarboxylate transporters; prostate cancer; tumor microenvironment.

Figure 3

Lactate modulates the tumor microenvironment and promotes PCa progression. PCa undergoes a metabolic shift to adapt to the energetic requirements and nutrient availability as the disease progresses. Once produced, lactate is secreted into the TME where it promotes extracellular matrix (ECM) remodeling, neo-angiogenesis, immune evasion, TME acidity to favor cancer cell migration, invasion, metastasis formation, and therapy resistance. DC = dendritic cell, CAFs = cancer-associated fibroblasts, ETC = electron transport chain, TAM = tumor associated fibroblast, TCA = tricarboxylic acid, TME = tumor microenvironment, Treg = regulatory T cells, Vertical red arrow means increase. This figure was created with BioRender.com with license rights.

Figure 1

PCa acquires glycolytic features during the progression to metastatic castration-resistant PCa (mCRPC). In the normal prostate, high zinc levels inhibit the activity of the enzyme m-aconitase, inducing a truncated TCA cycle and substantial secretion of citrate in the spermatic fluid. In primary PCa, zinc levels are significantly reduced, such that PCa cells re-activate the TCA cycle and display an oxidative phenotype. Citrate is oxidized in TCA or exported to the cytosol for FA synthesis. As the disease progresses to mCRPC, both the TME and the AR signaling promote the expression of glycolytic genes and the acquisition of a glycolytic phenotype, resulting in an increased uptake of glucose and lactate accumulation. Lactate can also be produced from glutamine through glutaminolysis (highlighted in blue). In castration-resistant PCa with neuroendocrine features (CRPC-NE) and aggressive variant PCa (AVPC), the increase in aerobic glycolysis seems to be driven by AR-independent mechanisms. A clear understanding is, however, still missing (depicted with “?” symbol). ADT = androgen deprivation therapy. PSA = Prostate Specific Antigen. Violet arrow indicates increase in PSA. This figure was created with BioRender.com with license rights.

Figure 2

HP [1-¹³C]pyruvate MRSI uncovers increased aerobic glycolysis in CRPC. Representative T2-weighted proton images of androgen-dependent (ADPC, top) and castration-resistant (CRPC, bottom) TRAMP tumors at baseline (left column) and five days post-castration (right column). A T2-weighted image, a spin echo based pulse sequence in magnetic resonance imaging, provides contrast based on the transverse relaxation property of the water molecule which is dictated by the tissue properties and is used to differentiate the tumor from the surrounding normal tissue. The spectrum of the HP lactate (Lac) and pyruvate (Pyr) is shown on the right of each T2-weighted proton image. The Lac/Pyr ratio calculated from a voxel (red square) is reported. Image from Sun J et al. [54] with the author’s permission.

Figure 4

Lactate shuttle between CAFs and PCa cells promotes castration resistance and disease progression. Lactate shuttling between CAFs and PCa cells: (i) promotes mitochondrial activity to fulfill PCa cells’ enhanced energetic needs, (ii) inhibits immune surveillance, and (iii) induces epigenetic-regulated lipid metabolism rewiring. This multifaceted role of the lactate shuttle sustains PCa survival in harsh environments (i.e., hypoxia) and the acquisition of PCa invasive features. AC = acetylation, ACC = acetyl-CoA carboxylase, ACLY = ATP citrate lyase, CAFs = cancer-associated fibroblasts, CAIX = hypoxia-regulated carbonic anhydrase IX, FASN = fatty acid synthase, GLUT-1 = glucose transporter 1, Lac = lactate, LD = lipid droplets, MCT-1 = monocarboxylate transporter 1, OXPHOS = oxidative phosphorylation, PCa = prostate cancer, Pyr = pyruvate, PLIN2 = perilipin 2, SIRT-1 = sirtuin 1, TCA = tricarboxylic acid. This figure was created with BioRender.com with license rights.

Figure 5

Diet, obesity, and lifestyle promote tumor metabolic rewiring. Diet, obesity, and lifestyle affect the gut microbiota and circulating/intra-tumor metabolite levels, promoting PCa progression. This figure was created with BioRender.com with license rights.

Figure 6

Non-invasive imaging of glucose uptake using ¹⁸F-FDG PET. Workflow of ¹⁸F-FDG PET in the clinical setting. ¹⁸F-FDG PET can provide useful information in the diagnostic workup and therapy decision making. CT = computerized tomography, ¹⁸F-FDG = [¹⁸F]fluorodeoxyglucose, mets = metastases, PET = positron emission tomography, PCa = prostate cancer. Vertical red arrow means increase, This figure was created with BioRender.com with license rights.

Figure 7

Non-invasive imaging of pyruvate-to-lactate conversion. Workflow of HP ¹³C pyruvate MRI in the clinical setting. HP ¹³C pyruvate MRI can provide useful information in the diagnostic workup and therapy decision making. HP = hyperpolarized, Lac = lactate, mets = metastases, MRI = magnetic resonance imaging, PCa = prostate cancer, Pyr = Pyruvate. Vertical red arrow means increase. This figure was created with BioRender.com with license rights.