HER2‑positive breast cancer that resists therapeutic drugs and ionizing radiation releases sphingomyelin‑based molecules to circulating blood serum

Monzen, Satoru; Tatara, Yota; Mariya, Yasushi; Chiba, Mitsuru; Wójcik, Andrzej; Lundholm, Lovisa

doi:10.3892/mco.2020.2140

Cited by 3 publications

(3 citation statements)

References 34 publications

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“…Several lines of research documented the role of surface membrane SM in tumorigenesis. First, changes in sphingolipids levels were established for several tumor cells and cell lines [ 52 – 57 ]. More specifically, level of SM in the outer leaflet of cell plasma membrane was reported to be significantly elevated in highly metastatic human prostatic adenocarcinoma cell lines compared to the lower metastatic variant [ 52 ].…”

Section: Tumor Immune Evasionmentioning

confidence: 99%

Cell surface sphingomyelin: key role in cancer initiation, progression, and immune evasion

2021

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Cell surface biochemical changes, notably excessive increase in outer leaflet sphingomyelin (SM) content, are important in cancer initiation, growth, and immune evasion. Innumerable reports describe methods to initiate, promote, or enhance immunotherapy of clinically detected cancer, notwithstanding the challenges, if not impossibility, of identification of tumor-specific, or associated antigens, the lack of tumor cell surface membrane expression of major histocompatibility complex (MHC) class I alpha and β2 microglobulin chains, and lack of expression or accessibility of Fas and other natural killer cell immune checkpoint molecules. Conversely, SM synthesis and hydrolysis are increasingly implicated in initiation of carcinogenesis and promotion of metastasis. Surface membrane SM readily forms inter- and intra- molecular hydrogen bond network, which excessive tightness would impair cell-cell contact inhibition, inter- and intra-cellular signals, metabolic pathways, and susceptibility to host immune cells and mediators. The present review aims at clarifying the tumor immune escape mechanisms, which face common immunotherapeutic approaches, and attracting attention to an entirely different, neglected, key aspect of tumorigenesis associated with biochemical changes in the cell surface that lead to failure of contact inhibition, an instrumental tumorigenesis mechanism. Additionally, the review aims to provide evidence for surface membrane SM levels and roles in cells resistance to death, failure to respond to growth suppressor signals, and immune escape, and to suggest possible novel approaches to cancer control and cure.

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Section: Tumor Immune Evasionmentioning

confidence: 99%

Cell surface sphingomyelin: key role in cancer initiation, progression, and immune evasion

2021

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“…Evaluating whether SL plasma levels can be predictive determinants for the SL status in tumors was the main objective of the metabolomic approach applied in two studies. Indeed, Miolo et al [122] identified circulating spermidine and tryptophan as potential markers associated with the complete pathological response to trastuzumab-paclitaxel neoadjuvant therapy in HER2+ BC.More interestingly, Monzen S. et al [123] recently reported not only a parallel expression intensity of HER2 and nSMase2, possibly connected to cell communication by extracellular vesicles (EVs) [124], but also that the serum concentration of four SM species [SM 24:1, SM C26:0, hydroxySM C16:1 and hydroxySM C24:1] were inversely related to the accumulation of nSMase2 in HER2+ cancer tissues from a patient who exhibited complete therapeutic resistance to monoclonal-anti-HER2 antibody therapy, chemotherapy and radiotherapy after mastectomy. Clearly, further and detailed analyses are needed on a larger number of patients.…”

Section: Future Perspectivesmentioning

confidence: 99%

The Critical Impact of Sphingolipid Metabolism in Breast Cancer Progression and Drug Response

Corsetto

Zava

Rizzo

et al. 2023

IJMS

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Breast cancer is the second leading cause of cancer-related death in women in the world, and its management includes a combination of surgery, radiation therapy, chemotherapy, and immunotherapy, whose effectiveness depends largely, but not exclusively, on the molecular subtype (Luminal A, Luminal B, HER2+ and Triple Negative). All breast cancer subtypes are accompanied by peculiar and substantial changes in sphingolipid metabolism. Alterations in sphingolipid metabolite levels, such as ceramides, dihydroceramide, sphingosine, sphingosine-1-phosphate, and sphingomyelin, as well as in their biosynthetic and catabolic enzymatic pathways, have emerged as molecular mechanisms by which breast cancer cells grow, respond to or escape therapeutic interventions and could take on diagnostic and prognostic value. In this review, we summarize the current landscape around two main themes: 1. sphingolipid metabolites, enzymes and transport proteins that have been found dysregulated in human breast cancer cells and/or tissues; 2. sphingolipid-driven mechanisms that allow breast cancer cells to respond to or evade therapies. Having a complete picture of the impact of the sphingolipid metabolism in the development and progression of breast cancer may provide an effective means to improve and personalize treatments and reduce associated drug resistance.

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“…114 Numerous articles have documented the role of excessive content of surface membrane sphingomyelin and down-regulation of the membrane-associated neutral sphingomyelinase in tumor immune evasion, initiation, growth and drug resistance of hepatic, breast, ovarian, brain, and bone cancer growth and metastasis. 4,[115][116][117][118][119][120][121][122] In that context, it is timely to recall that potent activators of neutral sphingomyelinases, notably long-chain polyunsaturated fatty acids such as arachidonic acid, are increasingly documented as safe and efficacious in prevention and therapy of clinicallydetected tumors. 4,[123][124][125]…”

Section: Future Directionsmentioning

confidence: 99%

The Stroma and Tumor Microenvironment Are Not the Most Instrumental Players in Tumor Cells Immune Evasion, Growth, and Resistance to Therapy

Tallima¹,

Ridi²

2022

Preprint

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The central reason behind emergence of clinically-detectable tumors is evasion from immune surveillance due to lack of cancer cells surface membrane expression of tumor-specific peptides in association with MHC class I molecules, concealment of natural killer cells-activating molecules, and absence of inflammation resulting from inefficient stimulation of innate immunity receptors and co-stimulatory molecules. The tumor microenvironment (TME) also contributes to tumor initiation, progression and resistance to therapeutic interventions because of its dense, fibrogenic, barrier-like composition, aberrant vasculature, and production of cytokines and chemokines responsible for recruitment of immune suppressive cells, notably myeloid-derived suppressor cells, M2 macrophages, regulatory T cells, extracellular trap-forming neutrophils, and cancer-associated fibroblasts. We herein show that the relentless efforts and strategies to overcome the TME elusive tumor-promoting impact produced contrasting, opposed, controversial effects, characterized by limited efficacy and proven adversity, and most importantly deterred from attempts to discover and counteract the fundamental inherent mechanisms initiating, and not consequent to, carcinogenesis.

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HER2‑positive breast cancer that resists therapeutic drugs and ionizing radiation releases sphingomyelin‑based molecules to circulating blood serum

Cited by 3 publications

References 34 publications

Cell surface sphingomyelin: key role in cancer initiation, progression, and immune evasion

Cell surface sphingomyelin: key role in cancer initiation, progression, and immune evasion

The Critical Impact of Sphingolipid Metabolism in Breast Cancer Progression and Drug Response

The Stroma and Tumor Microenvironment Are Not the Most Instrumental Players in Tumor Cells Immune Evasion, Growth, and Resistance to Therapy

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