The implications of signaling lipids in cancer metastasis

Abstract Metastasis is the most malignant stage of cancer. Lipid metabolic abnormalities are now increasingly recognized as characteristics of cancer cells. The accumulation of certain lipid species, such as signaling lipids, due to the avidity of lipid metabolism may be a causal factor of tumor malignant progression and metastatic behavior. In this review, we first describe signaling lipids implicated in cancer migration, invasion and metastasis. Next, we summarize the regulatory signaling hubs of lipid anabolic and catabolic metabolism. We then address lipid-rich circulating tumor cells (CTCs) and the lipid composition of exosomes budded off from tumor cells. We also present advances in targeting the regulatory hubs of lipid metabolism and signaling lipids in cancer therapy. Given the complexity of metabolic disorders in cancer, the development of significant portfolios of approaches to target signaling lipids by the integration of multiple chemical modulations, as well as molecular imaging modalities, should offer promising strategies for cancer therapy. Introduction Metabolic reprogramming is now acknowledged as a core hallmark of cancer, characterized by functional dependence on glucose and glutamine catabolic pathways. Tumors often share a common feature of uncontrolled cell proliferation; therefore, they must efficiently produce biomass components and energy for expansion and further dissemination1,2,3,4. Lipid metabolic abnormalities are now increasingly recognized as a signature of cancer cells5,6,7. Highly proliferative cancer cells show enhanced lipid avidity by either increasing the uptake of exogenous lipids and lipoproteins or upregulating de novo lipid synthesis5. Activation of a variety of oncogenic pathways deregulates lipid metabolic processes, leading to the accumulation of certain lipid species such as signaling lipids. These bioactive lipids can serve as secondary signaling messengers to coordinate signal transduction cascades and to modulate a variety of carcinogenic processes, including cell proliferation, survival, chemoresistance and metastatic formation. Moreover, in the tumor microenvironment, noncancerous cells, such as endothelial cells, inflammatory cells, immune cells, fibroblasts and adipocytes, also play crucial roles in tumor expansion and malignant progression. Lipid autacoids, which are mainly composed of signaling lipids, can potentially target different cellular components in tumor microenvironments and conduct intercellular communication between cancerous and noncancerous cells8. Tumor metastasis remains the major cause of cancer-related mortality, highlighting the importance of exploring new strategies to prevent and control tumor metastasis9. Current research on metabolism has been mostly focused on the primary tumor, while metabolic adjustments during each step of metastasis have received less attention10. In this review, we first discuss signaling lipids implicated in cancer migration, invasion and metastasis. Next, we summarize the regulatory hubs of anabolic and catabolic lipid metabolism. We address lipid-rich CTCs and the lipid composition of exosomes budded off from tumor cells. We also present advances in targeting the regulatory hubs of lipid metabolism and signaling lipids in cancer therapy (Table 1)11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27. Table 1 Pharmacological tools to manipulate oncogenic regulatory pathways and lipid mediators associated with cancer metastasis Full size table Signaling lipids associated with cancer metastasis In cancer cells driven by oncogenic signaling or genetic mutation of critical metabolic enzymes, the balance of metabolite homeostasis is disrupted28. Accumulation of signaling lipids, including eicosanoids, phosphoinositides, sphingolipids, and fatty acids, alters the cellular biochemical foundation and might be a causal factor of tumor malignant progression and metastasis29,30,31,32,33 (Fig. 1). Fig. 1: Schematic of signaling lipids implicated in cancer invasive and metastatic progression and the mechanism of action. CTC circulating tumor cell, EET epoxyeicosatrienoic acid, FA fatty acid, FABP fatty acid-binding protein, LT leukotriene, PI phosphatidyl inositides, S1P sphingosine-1-phosphate Full size image Eicosanoids Arachidonic acids are metabolized through the cyclooxygenase, lipoxygenase (LOX) and P450 epoxygenase (EPOX) pathways to generate eicosanoids, which include prostanoids, leukotrienes, hydroxyeicosatetraenoic acids, epoxyeicosatrienoic acids (EETs) and hydroperoxyeicosatetraenoic acids34,35. Since prostanoids, such as the proinflammatory PGE2, have long been documented for their prominent role in promoting tumor growth and metastasis20,35,36,37,38,39,40,41,42, we will focus on the leukotrienes and EET species of eicosanoids in this review. Leukotrienes (LTs) LTs are generated by Alox5 (arachidonate 5-lipoxygenase) and are primarily produced in stimulated leukocytes. Although in co (...truncated)