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20 pages, 4634 KiB

Open AccessArticle

Low Serum Cholesterol Level Is a Significant Prognostic Factor That Improves CLL-IPI in Chronic Lymphocytic Leukaemia

by Rui Gao, Kaixin Du, Jinhua Liang, Yi Xia, Jiazhu Wu, Yue Li, Bihui Pan, Li Wang, Jianyong Li and Wei Xu

Int. J. Mol. Sci. 2023, 24(8), 7396; https://doi.org/10.3390/ijms24087396 - 17 Apr 2023

Cited by 4 | Viewed by 1442

Abstract

Hypocholesterolaemia is associated with elevated cancer risk and mortality, yet the relation between chronic lymphocytic leukaemia (CLL) and serum lipid profile remains unclear. Our study aims to evaluate the prognostic value of cholesterol levels in CLL and develop a prognostic nomogram that incorporates [...] Read more.

Hypocholesterolaemia is associated with elevated cancer risk and mortality, yet the relation between chronic lymphocytic leukaemia (CLL) and serum lipid profile remains unclear. Our study aims to evaluate the prognostic value of cholesterol levels in CLL and develop a prognostic nomogram that incorporates lipid metabolism. We enrolled 761 newly diagnosed CLL patients and separated them into either derivation (n = 507) or validation (n = 254) cohorts. The prognostic nomogram was constructed through multivariate Cox regression analyses, with performance evaluated using C-index, the area under the curve, calibration, and decision curve analyses. Decreased total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) at diagnosis were significantly associated with worse time to first treatment (TTFT) and cancer-specific survival (CSS), and simultaneously, low HDL-C with low LDL-C was identified as an independent prognostic indicator for both TTFT and CSS. CLL patients achieving complete or partial remission post-chemotherapy had significantly increased TC, HDL-C, and LDL-C levels compared with the baseline, and post-therapeutic HDL-C and LDL-C elevation correlated with favourable survival. The prognostic nomogram augmenting the CLL international prognostic index with low cholesterol levels yielded higher predictive accuracy and discrimination capacity for both 3-year and 5-year CSS. In conclusion, cholesterol profiles can be used as a cheap and readily accessible tool for predicting prognosis in CLL practice. Full article

(This article belongs to the Special Issue Lipid as a Cancer Therapeutic Target 2.0)

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13 pages, 3119 KiB

Open AccessArticle

The Effect of Cholesterol in MCF7 Human Breast Cancer Cells

by Elisabetta Albi, Martina Mandarano, Samuela Cataldi, Maria Rachele Ceccarini, Federico Fiorani, Tommaso Beccari, Angelo Sidoni and Michela Codini

Int. J. Mol. Sci. 2023, 24(6), 5935; https://doi.org/10.3390/ijms24065935 - 21 Mar 2023

Cited by 4 | Viewed by 1864

Abstract

In the last decade, cholesterol level has been implicated in several types of cancer, including breast cancer. In the current study, we aimed to investigate the condition of lipid depletion, hypocholesterolemia or hypercholesterolemia reproduced in vitro to analyze the response of different human [...] Read more.

In the last decade, cholesterol level has been implicated in several types of cancer, including breast cancer. In the current study, we aimed to investigate the condition of lipid depletion, hypocholesterolemia or hypercholesterolemia reproduced in vitro to analyze the response of different human breast cancer cells. Thus, MCF7 as the luminal A model, MB453 as the HER2 model and MB231 as the triple-negative model were used. No effect on cell growth and viability was detected in MB453 and MB231 cells. In MCF7 cells, hypocholesterolemia (1) reduced cell growth, and Ki67 expression; (2) increased ER/PgR expression; (3) stimulated the 3-Hydroxy-3-Methylglutaryl-CoA reductase and neutral sphingomyelinase and; (4) stimulated the expression of CDKN1A gene coding cyclin-dependent kinase inhibitor 1A protein, GADD45A coding growth arrest and DNA-damage-inducible alpha protein and, PTEN gene coding phosphatase and tensin homolog. All these effects were exacerbated by the lipid-depleted condition and reversed by the hypercholesterolemic condition. The relationship between cholesterol level and sphingomyelin metabolism was demonstrated. In summary, our data suggest that cholesterol levels should be controlled in luminal A breast cancer. Full article

(This article belongs to the Special Issue Lipid as a Cancer Therapeutic Target 2.0)

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18 pages, 2237 KiB

Open AccessArticle

Minibody-Based and scFv-Based Antibody Fragment-Drug Conjugates Selectively Eliminate GD2-Positive Tumor Cells

by Daniel V. Kalinovsky, Irina V. Kholodenko, Alexey V. Kibardin, Igor I. Doronin, Elena V. Svirshchevskaya, Dmitriy Y. Ryazantsev, Maria V. Konovalova, Fedor N. Rozov, Sergey S. Larin, Sergey M. Deyev and Roman V. Kholodenko

Int. J. Mol. Sci. 2023, 24(2), 1239; https://doi.org/10.3390/ijms24021239 - 08 Jan 2023

Cited by 8 | Viewed by 3085

Abstract

Ganglioside GD2 is a well-established target expressed on multiple solid tumors, many of which are characterized by low treatment efficiency. Antibody-drug conjugates (ADCs) have demonstrated marked success in a number of solid tumors, and GD2-directed drug conjugates may also hold strong therapeutic potential. [...] Read more.

Ganglioside GD2 is a well-established target expressed on multiple solid tumors, many of which are characterized by low treatment efficiency. Antibody-drug conjugates (ADCs) have demonstrated marked success in a number of solid tumors, and GD2-directed drug conjugates may also hold strong therapeutic potential. In a recent study, we showed that ADCs based on the approved antibody dinutuximab and the drugs monomethyl auristatin E (MMAE) or F (MMAF) manifested potent and selective cytotoxicity in a panel of tumor cell lines and strongly inhibited solid tumor growth in GD2-positive mouse cancer models. Here, we employed two different GD2-binding moieties–minibodies and scFv fragments that carry variable antibody domains identical to those of dinutuximab, and site-directly conjugated them to MMAE or MMAF by thiol-maleimide chemistry with drug-to-antibody ratios (DAR) of 2 and 1, respectively. Specific binding of the antibody fragment-drug conjugates (FDCs) to GD2 was confirmed in direct ELISA, flow cytometry, and confocal microscopy. Selective cytotoxic and cytostatic effects of the conjugates were observed in GD2-positive but not GD2-negative neuroblastoma and melanoma cell lines. Minibody-based FDCs demonstrated more pronounced cytotoxic effects and stronger antigen binding compared to scFv-based FDCs. The developed molecules may offer considerable practical benefit, since antibody fragment-drug conjugates are capable of enhancing therapeutic efficacy of ADCs by improving their pharmacokinetic characteristics and reducing side effects. Full article

(This article belongs to the Special Issue Lipid as a Cancer Therapeutic Target 2.0)

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22 pages, 3724 KiB

Open AccessArticle

Multifunctional Role of Lipids in Modulating the Tumorigenic Properties of 4T1 Breast Cancer Cells

by Yuanyuan He, Somayeh Rezaei, Raimundo Fernandes de Araújo Júnior, Luis J. Cruz and Christina Eich

Int. J. Mol. Sci. 2022, 23(8), 4240; https://doi.org/10.3390/ijms23084240 - 11 Apr 2022

Cited by 5 | Viewed by 2670

Abstract

Tumor growth and progression are linked to an altered lipid metabolism in the tumor microenvironment (TME), including tumor cells and tumor-associated macrophages (TAMs). A growing number of lipid metabolism targeting drugs have shown efficacy in anti-tumor therapy. In addition, exogenously applied lipids and [...] Read more.

Tumor growth and progression are linked to an altered lipid metabolism in the tumor microenvironment (TME), including tumor cells and tumor-associated macrophages (TAMs). A growing number of lipid metabolism targeting drugs have shown efficacy in anti-tumor therapy. In addition, exogenously applied lipids and lipid analogues have demonstrated anti-tumor activities in several cancers, including breast cancer. In this study, we investigated the anti-tumor efficacies of the natural lipids palmitic acid (PA), sphingomyelin (SM), ceramide (Cer) and docosahexaenoic acid (DHA) on breast cancer cells. All tested lipids reduced the malignancy of breast cancer cells in vitro by impairing cell proliferation, migration and invasiveness. PA showed superior anti-tumor properties, as it additionally impaired cancer cell viability by inducing apoptosis, without affecting healthy cells. Co-culture experiments further demonstrated that Cer and PA reduced the immunosuppressive phenotype of M2 macrophages and the M2 macrophage-promoted the epithelial–mesenchymal transition (EMT) and migration of breast cancer cells. At the molecular level, this coincided with the up-regulation of E-cadherin. Our results highlight a powerful role for exogenously applied PA and Cer in reducing breast cancer tumorigenicity by simultaneously targeting cancer cells and M2 macrophages. Our findings support the notion that lipids represent alternative biocompatible therapeutic agents for breast cancer. Full article

(This article belongs to the Special Issue Lipid as a Cancer Therapeutic Target 2.0)

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20 pages, 2628 KiB

Open AccessArticle

A UHPLC-Mass Spectrometry View of Human Melanocytic Cells Uncovers Potential Lipid Biomarkers of Melanoma

by Arantza Perez-Valle, Beatriz Abad-García, Olatz Fresnedo, Gabriel Barreda-Gómez, Patricia Aspichueta, Aintzane Asumendi, Egoitz Astigarraga, José A. Fernández, María Dolores Boyano and Begoña Ochoa

Int. J. Mol. Sci. 2021, 22(21), 12061; https://doi.org/10.3390/ijms222112061 - 08 Nov 2021

Cited by 4 | Viewed by 2500

Abstract

Melanoma is the deadliest form of skin cancer due to its ability to colonize distant sites and initiate metastasis. Although these processes largely depend on the lipid-based cell membrane scaffold, our understanding of the melanoma lipid phenotype lags behind most other aspects of [...] Read more.

Melanoma is the deadliest form of skin cancer due to its ability to colonize distant sites and initiate metastasis. Although these processes largely depend on the lipid-based cell membrane scaffold, our understanding of the melanoma lipid phenotype lags behind most other aspects of this tumor cell. Here, we examined a panel of normal human epidermal and nevus melanocytes and primary and metastatic melanoma cell lines to determine whether distinctive cell-intrinsic lipidomes can discern non-neoplastic from neoplastic melanocytes and define their metastatic potential. Lipidome profiles were obtained by UHPLC-ESI mass-spectrometry, and differences in the signatures were analyzed by multivariate statistical analyses. Significant and highly specific changes in more than 30 lipid species were annotated in the initiation of melanoma, whereas less numerous changes were associated with melanoma progression and the non-malignant transformation of nevus melanocytes. Notably, the “malignancy lipid signature” features marked drops in pivotal membrane lipids, like sphingomyelins, and aberrant elevation of ether-type lipids and phosphatidylglycerol and phosphatidylinositol variants, suggesting a previously undefined remodeling of sphingolipid and glycerophospholipid metabolism. Besides broadening the molecular definition of this neoplasm, the different lipid profiles identified may help improve the clinical diagnosis/prognosis and facilitate therapeutic interventions for cutaneous melanoma. Full article

(This article belongs to the Special Issue Lipid as a Cancer Therapeutic Target 2.0)

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Review

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15 pages, 1784 KiB

Open AccessReview

Epigenetic Regulation Mediated by Sphingolipids in Cancer

by Nicolò Bozzini, Sofia Avnet, Nicola Baldini and Margherita Cortini

Int. J. Mol. Sci. 2023, 24(6), 5294; https://doi.org/10.3390/ijms24065294 - 10 Mar 2023

Cited by 1 | Viewed by 1379

Abstract

Epigenetic changes are heritable modifications that do not directly affect the DNA sequence. In cancer cells, the maintenance of a stable epigenetic profile can be crucial to support survival and proliferation, and said profile can differ significantly from that of healthy cells. The [...] Read more.

Epigenetic changes are heritable modifications that do not directly affect the DNA sequence. In cancer cells, the maintenance of a stable epigenetic profile can be crucial to support survival and proliferation, and said profile can differ significantly from that of healthy cells. The epigenetic profile of a cancer cell can be modulated by several factors, including metabolites. Recently, sphingolipids have emerged as novel modulators of epigenetic changes. Ceramide and sphingosine 1-phosphate have become well known in cancer due to activating anti-tumour and pro-tumour signalling pathways, respectively, and they have recently been shown to also induce several epigenetic modifications connected to cancer growth. Additionally, acellular factors in the tumour microenvironment, such as hypoxia and acidosis, are now recognised as crucial in promoting aggressiveness through several mechanisms, including epigenetic modifications. Here, we review the existing literature on sphingolipids, cancer, and epigenetic changes, with a focus on the interaction between these elements and components of the chemical tumour microenvironment. Full article

(This article belongs to the Special Issue Lipid as a Cancer Therapeutic Target 2.0)

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25 pages, 1673 KiB

Open AccessReview

Lipids as Targets for Renal Cell Carcinoma Therapy

by Bisera Stepanovska Tanturovska, Roxana Manaila, Doriano Fabbro and Andrea Huwiler

Int. J. Mol. Sci. 2023, 24(4), 3272; https://doi.org/10.3390/ijms24043272 - 07 Feb 2023

Cited by 1 | Viewed by 2615

Abstract

Kidney cancer is among the top ten most common cancers to date. Within the kidney, renal cell carcinoma (RCC) is the most common solid lesion occurring. While various risk factors are suspected, including unhealthy lifestyle, age, and ethnicity, genetic mutations seem to be [...] Read more.

Kidney cancer is among the top ten most common cancers to date. Within the kidney, renal cell carcinoma (RCC) is the most common solid lesion occurring. While various risk factors are suspected, including unhealthy lifestyle, age, and ethnicity, genetic mutations seem to be a key risk factor. In particular, mutations in the von Hippel–Lindau gene (Vhl) have attracted a lot of interest since this gene regulates the hypoxia inducible transcription factors HIF-1α and HIF-2α, which in turn drive the transcription of many genes that are important for renal cancer growth and progression, including genes involved in lipid metabolism and signaling. Recent data suggest that HIF-1/2 are themselves regulated by bioactive lipids which make the connection between lipids and renal cancer obvious. This review will summarize the effects and contributions of the different classes of bioactive lipids, including sphingolipids, glycosphingolipids, eicosanoids, free fatty acids, cannabinoids, and cholesterol to renal carcinoma progression. Novel pharmacological strategies interfering with lipid signaling to treat renal cancer will be highlighted. Full article

(This article belongs to the Special Issue Lipid as a Cancer Therapeutic Target 2.0)

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16 pages, 661 KiB

Open AccessReview

Lipid Metabolic Alterations in KRAS Mutant Tumors: Unmasking New Vulnerabilities for Cancer Therapy

by Maria Saliakoura and Georgia Konstantinidou

Int. J. Mol. Sci. 2023, 24(2), 1793; https://doi.org/10.3390/ijms24021793 - 16 Jan 2023

Cited by 2 | Viewed by 2151

Abstract

KRAS is one of the most commonly mutated genes, an event that leads to development of highly aggressive and resistant to any type of available therapy tumors. Mutated KRAS drives a complex network of lipid metabolic rearrangements to support the adaptation of cancer [...] Read more.

KRAS is one of the most commonly mutated genes, an event that leads to development of highly aggressive and resistant to any type of available therapy tumors. Mutated KRAS drives a complex network of lipid metabolic rearrangements to support the adaptation of cancer cells to harsh environmental conditions and ensure their survival. Because there has been only a little success in the continuous efforts of effectively targeting KRAS-driven tumors, it is of outmost importance to delineate the exact mechanisms of how they get rewired, leading to this distinctive phenotype. Therefore, the aim of this review is to summarize the available data acquired over the last years with regard to the lipid metabolic regulation of KRAS-driven tumors and elucidate their specific characteristics in an attempt to unravel novel therapeutic targets. Full article

(This article belongs to the Special Issue Lipid as a Cancer Therapeutic Target 2.0)

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10 pages, 901 KiB

Open AccessReview

Hypercholesterolemia in Cancer and in Anorexia Nervosa: A Hypothesis for a Crosstalk

by Giulia Gizzi, Samuela Cataldi, Claudia Mazzeschi, Elisa Delvecchio, Maria Rachele Ceccarini, Michela Codini and Elisabetta Albi

Int. J. Mol. Sci. 2022, 23(13), 7466; https://doi.org/10.3390/ijms23137466 - 05 Jul 2022

Cited by 3 | Viewed by 2417

Abstract

The relationship between cholesterol and cancer has been widely demonstrated. Clinical studies have shown changes in blood cholesterol levels in cancer patients. In parallel, basic research studies have shown that cholesterol is involved in the mechanisms of onset and progression of the disease. [...] Read more.

The relationship between cholesterol and cancer has been widely demonstrated. Clinical studies have shown changes in blood cholesterol levels in cancer patients. In parallel, basic research studies have shown that cholesterol is involved in the mechanisms of onset and progression of the disease. On the other hand, anorexic patients have high cholesterol levels and a high susceptibility to cancer. In this review, we first present a brief background on the relations among nutrition, eating disorders and cancer. Using several notable examples, we then illustrate the changes in cholesterol in cancer and in anorexia nervosa, providing evidence for their important relationship. Finally, we show a new possible link between cholesterol disorder in cancer and in anorexia nervosa. Full article

(This article belongs to the Special Issue Lipid as a Cancer Therapeutic Target 2.0)

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