Inflammation is part of our body’s response to tissue injury and pathogens. It helps to recruit various immune cells to the site of inflammation and activates the production of mediators to mobilize systemic protective processes. However, chronic inflammation can increase the risk of diseases like cancer. Apart from cytokines and chemokines, lipid mediators, particularly sphingosine-1-phosphate (S1P) and ceramide-1-phosphate (C1P), contribute to inflammation and cancer. S1P is an important player in inflammation-associated colon cancer progression. On the other hand, C1P has been recognized to be involved in cancer cell growth, migration, survival, and inflammation. However, whether C1P is involved in inflammation-associated cancer is not yet established. In contrast, few studies have also suggested that S1P and C1P are involved in anti-inflammatory pathways regulated in certain cell types. Ceramide is the substrate for ceramide kinase (CERK) to yield C1P, and sphingosine is phosphorylated to S1P by sphingosine kinases (SphKs). Biological functions of sphingolipid metabolites have been studied extensively. Ceramide is associated with cell growth inhibition and enhancement of apoptosis while S1P and C1P are associated with enhancement of cell growth and survival. Altogether, S1P and C1P are important regulators of ceramide level and cell fate. This review focuses on S1P and C1P involvement in inflammation and cancer with emphasis on recent progress in the field.

The sialyltransferase ST6GAL1 that adds α2–6 linked sialic acids to N-glycans of cell surface and secreted glycoproteins is prominently associated with many human cancers. Tumor-native ST6GAL1 promotes tumor cell behaviors such as invasion and resistance to cell stress and chemo- and radio-treatments. Canonically, ST6GAL1 resides in the intracellular secretory apparatus and glycosylates nascent glycoproteins in biosynthetic transit. However, ST6GAL1 is also released into the extracellular milieu and extracellularly remodels cell surface and secreted glycans. The impact of this non-canonical extrinsic mechanism of ST6GAL1 on tumor cell pathobiology is not known. We hypothesize that ST6GAL1 action is the combined effect of natively expressed sialyltransferase acting cell-autonomously within the ER-Golgi complex and sialyltransferase from extracellular origins acting extrinsically to remodel cell-surface glycans. We found that shRNA knockdown of intrinsic ST6GAL1 expression resulted in decreased ST6GAL1 cargo in the exosome-like vesicles as well as decreased breast tumor cell growth and invasive behavior in 3D in vitro cultures. Extracellular ST6GAL1, present in cancer exosomes or the freely soluble recombinant sialyltransferase, compensates for insufficient intrinsic ST6GAL1 by boosting cancer cell proliferation and increasing invasiveness. Moreover, we present evidence supporting the existence novel but yet uncharacterized cofactors in the exosome-like particles that potently amplify extrinsic ST6GAL1 action, highlighting a previously unknown mechanism linking this enzyme and cancer pathobiology. Our data indicate that extracellular ST6GAL1 from remote sources can compensate for cellular ST6GAL1-mediated aggressive tumor cell proliferation and invasive behavior and has great clinical potential for extracellular ST6GAL1 as these molecules are in the extracellular space should be easily accessible targets.

Triple‑negative breast cancer (TNBC) cells form angiogenesis‑independent vessel‑like structures to survive, known as vasculogenic mimicry (VM), contributing to a poor prognosis for cancer patients. Nuclear localized class I histone deacetylases (HDACs) enzymes, particularly HDACs 1, 2, 3 deacetylate chromatin histones, are overexpressed in cancers and epigenetically regulate the expression of genes involved in cancer initiation and progression. The specific HDAC inhibitor, entinostat, has been shown to attenuate tumor progression and metastasis in TNBC. In this study, we hypothesized that entinostat would enhance the expression of anti‑angiogenic and tumor suppressor genes and would thus suppress VM structures in TNBC cells in a 3D Matrigel cell culture preclinical model. Our data indicated that invasive triple‑negative MDA‑MB‑231, LM2‑4 and BT‑549 breast cancer cells, but not poorly invasive luminal MCF‑7 cells, efficiently underwent matrix‑associated VM formation. Approximately 80% of TNBC cells with the stem cell phenotype potential formed vessel‑like structures when mixed with Matrigel and cultured in the low attachment tissue culture plate. The molecular mechanisms of VM formation are rather complex, while angiogenesis inhibitor genes are downregulated and pro‑angiogenesis genes are upregulated in VM‑forming cells. Our data revealed that treatment of the TNBC VM phenotype cells with entinostat epigenetically led to the re‑expression of the anti‑angiogenic genes, serpin family F member 1 (SERPINF1) and thrombospondin 2 (THBS2), and to that of the tumor suppressor genes, phosphatase and tensin homolog (PTEN) and p21, and reduced VM structures. We also found that treatment of the TNBC VM phenotype cells with entinostat downregulated the expression of vascular endothelial growth factor A (VEGF‑A), and that of the epithelial‑mesenchymal transition (EMT)‑related genes, Vimentin and β‑catenin. METABIRC and TCGA breast cancer cohort mRNA expression data analysis revealed that a high expression of the anti‑angiogenesis‑associated genes, THBS2, SERPINF1 and serpin family B member 5 (SERPINB5), and of the tumor suppressor gene, PTEN, was associated with a better overall survival (OS) of breast cancer patients. Taken together, the findings of this study demonstrate that HDACs 1, 2, 3 partly contribute to VM formation in TNBC cells; thus, HDACs may be an important therapeutic target for TNBC.

Sphingosine kinase 2 (SphK2) is known to phosphorylate the nuclear sphingolipid metabolite to generate sphingosine‐1‐phosphate (S1P). Nuclear S1P is involved in epigenetic regulation of gene expression; however, the underlying mechanisms are not well understood. In this work, we have identified the role of nuclear S1P and SphK2 in regulating hypoxia‐responsive master transcription factors hypoxia‐inducible factor (HIF)‐1α/2α, and their functions in breast cancer, with a focus on triple‐negative breast cancer (TNBC). We have shown SphK2 is associated with HIF‐1α in protein complexes, and is enriched at the promoters of HIF target genes, including vascular endothelial growth factor (VEGF), where it enhances local histone H3 acetylation and transcription. S1P specifically binds to the PAS domains of HIF‐1α. SphK2, and HIF‐1α expression levels are elevated in metastatic estrogen receptor‐positive (ER+) and TNBC clinical tissue specimens compared to healthy breast tissue samples. To determine if S1P formation in the nucleus by SphK2 is a key regulator of HIF functions, we found using a preclinical TNBC xenograft mouse model, and an existing selective SphK2 inhibitor K‐145, that nuclear S1P, histone acetylation, HIF‐1α expression, and TNBC tumor growth were all reduced in vivo. Our results suggest that S1P and SphK2 in the nucleus are linked to the regulation of HIF‐1α/2α functions associated with breast cancer progression, and may provide potential therapeutic targets.

Brain metastases represent a substantial amount of morbidity and mortality in breast cancer (BC). Metastatic breast tumor cells committed to brain metastases are unique because they escape immune surveillance, can penetrate the blood-brain barrier, and also adapt to the brain tissue microenvironment (TME) for colonization and outgrowth. In addition, dynamic intracellular interactions between metastatic cancer cells and neighboring astrocytes in the brain are thought to play essential roles in brain tumor progression. A better understanding of the above mechanisms will lead to developing more effective therapies for brain metastases. Growing literature suggests autophagy, a conserved lysosomal degradation pathway involved in cellular homeostasis under stressful conditions, plays essential roles in breast tumor metastatic transformation and brain metastases. Cancer cells must adapt under various microenvironmental stresses, such as hypoxia, and nutrient (glucose) deprivation, in order to survive and progress. Clinical studies reveal that tumoral expression of autophagy-related proteins is higher in brain metastasis compared to primary breast tumors. In this review, we outline the molecular mechanisms underlying autophagy-mediated BC cell survival and metastasis to the brain.