Encyclopedia
Please note this is a comparison between Version 1 by Rosa Carmen López-Sánchez and Version 2 by Jason Zhu.
Lymphomas are a highly heterogeneous group of hematological neoplasms. Given their ethiopathogenic complexity, their classification and management can become difficult tasks; therefore, new approaches are continuously being sought. Metabolic reprogramming at the lipid level is a hot topic in cancer research, and sphingolipidomics has gained particular focus in this area due to the bioactive nature of molecules such as sphingoid bases, sphingosine-1-phosphate, ceramides, sphingomyelin, cerebrosides, globosides, and gangliosides. Sphingolipid metabolism has become especially exciting because they are involved in virtually every cellular process through an extremely intricate metabolic web; in fact, no two sphingolipids share the same fate. Unsurprisingly, a disruption at this level is a recurrent mechanism in lymphomagenesis, dissemination, and chemoresistance, which means potential biomarkers and therapeutical targets might be hiding within these pathways.
- lymphoma
- cancer
- lipid metabolism
- lipidomics
1. Sphingoid Bases
Sphingoid bases are the simplest sphingolipids. They include sphinganine (dihydrosphingosine), which is formed from the condensation of palmitoyl-CoA and serine, and sphingosine, which results from ceramide cleavage through a ceramidase [1][54]. Being the backbone of larger sphingolipids, their role in cancer has not received much attention; however, they are known to have antiproliferative properties by themselves, and can enhance chemosensitivity by inducing oxidative stress and upregulating p38 and JNK in TP53 positive lymphoma cells [2][3][4][5][55,56,57,58]. In DLBCL specifically, both sphingosine and sphinganine analogues induce cell death by promoting PARP cleavage, autophagy, and PKC inhibition [6][7][59,60].
2. Sphingosine-1-Phosphate
S1P is a metabolically active form of sphingosine which results from the action of a sphingosine kinase (SPHK) [8][1]. When it comes to cancer, it is probably the most widely recognized sphingolipid, and it is involved in the pathogenesis of multiple neoplasms, such as head and neck, breast, ovarian, colon, pancreatic, prostate, liver, and bile duct, among many others [9][10][11][12][13][14][61,62,63,64,65,66]. It is vigorously produced by both cancer cells and cells of the tumor microenvironment, such as tumor associated macrophages (TAMs), endothelium, and fibroblasts, creating a complex “inside-out” signaling hub which promotes invasion and metastasis due to its ability to induce cell proliferation and migration, angiogenesis, and tissue remodeling [15][16][17][18][19][20][67,68,69,70,71,72]. This is achieved through the upregulation of several proto-oncogenes, such as MYC, FOS, and ABL1 [21][22][23][24][73,74,75,76]; extracellular matrix regulators, such as urokinase, Matrix Metalloprotease 2 (MMP-2), MMP-7, and syndecan-1 [25][26][27][28][77,78,79,80]; inflammatory mediators, such as IL-22 [29][81]; and transcription factors/transcriptional regulators, such as STAT3, MRTF-A, YAP, and SNAI2 [14][30][31][16,66,82]. Additionally, it favors CTFG and EGFR activation, which promote cancer cell motility through ezrin-radixin-moesin phosphorylation [32][33][34][83,84,85]. Moreover, it is known that autotaxin, which is upregulated in many cancers, generates many bioactive lipids, including lysophosphatidic acid (LPA) and S1P, which subsequently stimulate COX2 and therefore eicosanoid synthesis, yielding inflammatory conditions ideal for a tumorigenic microenvironment [35][36][37][38][39][18,21,86,87,88]. Furthermore, S1P pathways are related to chemotherapy resistance by upregulating the Multidrug Resistance gene (MDR1) [40][89]. This observation is consistent with the fact that SPHK1 activity and Sphingosine-1-Phosphate Receptor (S1PR) signaling appear to confer resistance to chemotherapy-induced apoptosis in many cancer models, whereas S1P-lyase, which mediates S1P degradation, has the opposite effect [41][42][43][90,91,92].
As for lymphomas, SPHK overexpression has consistently been associated with a more aggressive disease [44][45][46][93,94,95]. In vitro evidence suggests that MCL cells can evade CD1d-mediated NKT cytotoxicity by upregulating SPHK1 [47][48][96,97]. Additionally, a recent report found that SPHK1 and S1P itself mediate a VEGF-independent mechanism of angiogenesis in DLBCL, which might explain why, although some preliminary data have suggested otherwise, classical anti-angiogenic drugs such as bevacizumab are mostly ineffective for NHL [49][50][51][98,99,100]. These data make SPHK an attractive therapeutical target. On the other hand, it has been shown that S1PR1 signaling promotes survival, proliferation, and migration of MCL and HL cells through a PI3K-dependent pathway, and might be useful as both a pharmacological target and an marker for aggressiveness [52][53][54][101,102,103]. In fact, tissular expression of S1PR1 has been associated with a worse prognosis in certain NHL, particularly primary testicular DLBCL [55][56][104,105]. Interestingly, immunohistochemical detection of different S1PR isotypes, migration integrins, chemokines, and homing receptors correlates with specific anatomical and tissular locations of B-cell lymphomas [57][58][59][106,107,108]. For instance, in MCL, S1PR1 mutations are present in up to 8.6% of cases, and mediate tumoral cell retention in the mantle zone [60][61][62][109,110,111]. S1PR1 staining might be, in fact, a useful immunohistochemical marker for MCL, especially if cyclin D1 staining, the current standard, is inconclusive [63][112]. Additionally, it has been shown that mutations at this level (S1PR1) are partly responsible for the transformation of follicular lymphoma (FL) into its most aggressive form [64][113]. Contrastingly, S1PR2 activation shows completely opposite effects. Research suggests that it regulates cell survival and migration mainly through Akt and CXCL12 attenuation. In fact, the TGF-β/SMAD1/S1PR2 pathway is recurrently inactivated in DLBCL due to either disabling mutations in its axis or FOXP1-mediated downregulation [65][66][67][114,115,116]. Moreover, it has been recently reported that some EBV-related lymphomas downregulate S1PR2, allowing the PI3-K/Akt/mTOR pathway to be constitutively activated [68][17]. Naturally, while S1PR1 blockade is potentially antilymphomagenic, S1PR2 deficient mice are prone to developing DLBCL [69][70][71][117,118,119]. These reports highlight the complex nature of sphingolipid-related molecular pathways, and stress the need to understand them.
3. Ceramide
Ceramide is the central molecule of sphingolipid metabolism. It can be obtained by the hydrolysis of more complex sphingolipids, mainly SM via sphingomyelinase, or de novo through sphinganine fatty acylation and subsequent desaturation [1][54]. The length of the fatty acid chain has a relevant functional impact, being that C16, C18, and C24 are the most cytotoxic endogenously produced species. These sphingolipids are able to induce cell death through multiple pathways, including necroptosis, autophagy, mitophagy, necrosis, and especially apoptosis [72][73][74][120,121,122]. Caspase-dependent cell death mechanisms are achieved through Fas–FasL interaction, mitochondrial pore induction, TXNIP and BCLX upregulation, Rb overexpression, and telomere shortening via glyceraldehyde-3-phosphate dehydrogenase inhibition [75][76][77][78][79][80][81][123,124,125,126,127,128,129]. Furthermore, they also exhibit anti-proliferative effects through the activation of ceramide-activated protein phosphatases (CAPPs), which downregulate several CDKs; and PKC-ζ, which further leads to Akt attenuation [41][82][90,130]. This last observation is in line with the fact that ceramide and diacylglycerol (DAG), a potent PKC activator and thus pro-tumoral molecule, are simultaneously, but inversely, regulated during the SM cycle[83][131]. Considering all of these potentially cytotoxic mechanisms, it is not surprising that many chemotherapeutic agents exert their effects partly through intracellular ceramide accumulation in the microenvironment, and within the tumor itself [84][132]. Unfortunately, cancer cells can develop resistance mechanisms against this pathway. Of note, it is known that acid ceramidase, which transforms ceramides back into sphingosine, is overexpressed in multiple cancers, such as head and neck, breast, prostate, melanoma, colon, glioblastoma, leukemia, and lung, where it promotes neosis, and mediates both chemoresistance and radioresistance [41][85][86][87][88][89][90][91][92][93][90,133,134,135,136,137,138,139,140,141]. Additionally, research suggests that the Ceramide Transfer Protein (CERT), which transports ceramide from the endoplasmic reticulum to the Golgi apparatus prior to its conversion to SM, might play a key role in antineoplastic resistance, as its downregulation has been shown to enhance chemosensitivity [94][142].
In the particular case of lymphomas, ceramides have been shown to contribute to IL-2 deprivation related cytotoxicity by degrading the apoptotic inhibitor IAP3 through cathepsin B in T-cell and NK lymphomas [95][143]. Additionally, it is known that some B-cell lymphomas can have mutations in FVT1 (KDSR), a gene that codes for 3-ketodihydrosphingosine reductase, which synthesizes dehydrosphinganine, a precursor of ceramide. The fact that this locus is in close proximity to the much more recognized BCL-2 suggests a synergic role in lymphomagenesis [96][144]. Nonetheless, it is worth mentioning that different lymphomas have different patterns of FVT1 alterations, therefore its metabolic implications are not the same. For instance, while some FL are known to overexpress FVT1, some DLBCL downregulate it. As a matter of fact, FVT1 expression might be useful to discriminate between germinal center (GC) DLBCL from non-GC DLBCL [97][145]. On a different note, blocking SPHK pathways, particularly via SPHK2, is cytotoxic to murine models of primary effusion lymphoma (PEL), a human herpesvirus 8-related neoplasm, due to the upregulation of ceramide synthase and subsequent accumulation of cytotoxic ceramide species that lead to apoptosis by viral lytic gene expression [98][99][146,147]. Additionally, ceramides have also been shown to induce cell death through caspase-independent mechanisms in MCL cells, possibly due to ROS associated necrosis and ATP depletion [100][101][102][148,149,150]. Similar effects have been observed after treatment with ceramide analogues and exogenous ceramide administration, which induce several tumor suppressor genes such as CCL3, RHOB, KLF6, and THBS1 [103][104][105][106][107][151,152,153,154,155]. Finally, it is worth mentioning that rituximab, the cornerstone of B-cell NHL treatment, activates sphingomyelinase upon its binding to CD20, leading to an increased production of ceramide, and therefore selectively inducing cytotoxic pathways in CD20+ cells [108][109][110][156,157,158]. Similarly, it has been observed that newer anti-CD20 antibodies, such as tositumomab, are more effective in inducing programed cell death in NHL by inducing homotypic adhesion and lysosomal leakage, both of which are mediated by ceramide [95][111][143,159].
4. Ceramide-1-Phosphate
Similar to sphingosine, ceramide can also undergo phosphorylation by a ceramide kinase (CK) to produce ceramide-1-phosphate (C1P), whose functions are analogue to those of S1P and opposite to ceramide, meaning it is mainly involved in cell growth, migration, proliferation, and survival, all of which translate into cancer invasion and metastasis [1][54]. C1P is probably the least researched sphingolipid in the cancer context, with only a few studies linking it to neuroblastoma, and pancreatic and breast carcinomas [112][160]. Oncogenic and dissemination mechanisms include the PI3K/Akt/mTOR, MEK/ERK, and Rho/ROCK signaling pathways [113][114][115][161,162,163]. Although some of the initial studies describing the ceramide-C1P pathway were performed in leukemia cells, there is currently no published research linking C1P to lymphomas or any other hematological malignancy whatsoever [116][164].
5. Sphingomyelin
SM is a membrane sphingolipid that is abundantly found in membrane rafts, and thus is essential for signal transduction. In fact, K-Ras localization, and therefore MAPK/RAS signaling, is regulated by plasma membrane SM concentration [117][118][165,166]. SM results from ceramide condensation with phosphocholine via sphingomyelin synthase (SMS) [119][8]. As its biosynthesis requires ceramide metabolism, one might assume that these sphingolipids should have opposite effects. However, its actual role in cancer is controversial, as it is involved in both pro-tumoral and antineoplastic settings [120][121][122][167,168,169]. This duality might be partially explained by its central role in DAG/ceramide balance [123][170]. For instance, SMS2 has been shown to promote breast cancer metastasis by enhancing epithelial-to-mesenchymal transition (EMT) via TGF-β/Smad signaling [124][171]. On the other hand, SM levels seem to be inversely correlated with many cancer types, such as lung and esophageal [112][123][160,170]. Furthermore, exogenous SM administration promotes PPAR-γ mediated Th2 and anti-inflammatory responses, which are protective against cancer, and enhances chemotherapy-induced cytotoxicity by promoting drug influx and bioavailability [85][125][126][127][133,172,173,174].
In lymphomas most research points towards a primarily pro-tumorigenic effect. In vitro models have shown that SMS overexpression induces apoptosis resistance through PI3K-Akt upregulation, and stimulates malignant proliferation by promoting transferrin endocytosis in a SM-dependent manner [128][175]. These findings are in line with the fact that SMS inhibition or blockade enhances cell death due to ceramide accumulation, and inhibits infiltration by hindering the NF-κB pathway, subsequently downregulating adhesion molecules such as ICAM-1 [121][129][168,176]. On a different note, a recent clinical study found that even though total serum SM was similar between healthy controls and patients with hematologic malignancies, there were significantly lower levels of odd chain saturated fatty acids (OCFA) in the latter, which is interesting, since OCFA have recently been reported to be protective against several neoplasms, probably due to their histone deacetylase 6 inhibitor activity [130][131][132][133][134][177,178,179,180,181]. Finally, it has been observed that some lipid fragments of SM, together with specific phospholipid patterns, such as increased phosphatidylinositol and phosphatidylcholine, are markers of R-CHOP resistant or relapsed cases and of hypoxic and/or necrotic regions within the tumor [135][53]. These findings align with the previous observation that some endogenously produced phosphatidyl-myoinositols serve as physiologic inhibitors of sphingomyelinase [136][182].
