Antitumor potential of anti-glycosphingolipid therapy

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Abstract

Currently, immuno-oncology is a rapidly developing field of medicine, primarily due to the integration of achievements in molecular biology and biotechnology (creation and production of modified cells and effector molecules), immunological physiology (understanding of subtle mechanisms of regulation of immune functions) and clinical medicine (adequate accompanying therapy, allowing manipulation of the patient’s immune system). A large number of tumors overexpress tumor-associated gangliosides (sialylated glycosphingolipids). For example, GD3, GD2 and GM2 are overexpressed in melanoma and neuroblastoma cells, increased expression of GD1a, GM1, GM2 is shown in carcinoma cells, GD2 is expressed by soft tissue sarcoma, osteogenic sarcoma and small cell lung cancer cells. The ratio of the number of gangliosides varies from one tumor type to another. In addition, gangliosides are found in neoplastic tissues that are not characteristic of normal transformed cells of this tissue. In particular, one such ganglioside is GD2. In normal cells, the expression of this ganglioside, as well as that of GM2, is restricted to nerve cells, but in the case of cancer transformation they are found in cells of malignant tumors. Numerous studies have shown that tumor-associated gangliosides arising from oncogenic transformation play a key role in invasion and metastasis of a number of tumors and induce tumor-associated angiogenesis. First of all, it has been established that tumor cells differ in the composition of gangliosides. the ganglioside composition of metastasis cells differs from the cells of the primary tumor focus and is characterized by a decrease in the content of complex gangliosides. Due to its high level of expression in a number of tumors and limited expression in normal tissues, ganglioside GD2 can be considered as an ideal potential target for the development of anti-tumor immunotherapies.

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About the authors

Svetlana A. Kulyova

Saint Petersburg State Pediatric Medical University; N.N. Petrov National Medical Research Center of Oncology

Author for correspondence.
Email: kulevadoc@yandex.ru
ORCID iD: 0000-0003-0390-8498
SPIN-code: 3441-4820

MD, PhD, Assistant Professor

Russian Federation, Saint Petersburg; Saint Petersburg

Vadim A. Khashuro

Saint Petersburg State Pediatric Medical University; Saint Petersburg State University

Email: kashuro@yandex.ru
ORCID iD: 0000-0002-7892-0048
SPIN-code: 3821-8062

MD, PhD, Assistant Professor

Russian Federation, Saint Petersburg; Saint Petersburg

Ekaterina G. Batocirenova

Saint Petersburg State Pediatric Medical University

Email: bkaterina2009@yandex.ru
ORCID iD: 0000-0003-3827-4579
SPIN-code: 5800-7966

MD, PhD in Biology

Russian Federation, Saint Petersburg

Gaziя A. Sachautdinov

Saint Petersburg State Pediatric Medical University; N.N. Petrov National Medical Research Center of Oncology

Email: derek2396@mail.ru
ORCID iD: 0000-0003-4795-6969
SPIN-code: 1421-4493

Postgraduate Student

Russian Federation, Saint Petersburg; Saint Petersburg

Yulia K. Semenova

Saint Petersburg State Pediatric Medical University

Email: semenova.julia1997@gmail.com
ORCID iD: 0000-0002-7600-4732

Postgraduate Student

Russian Federation, Saint Petersburg

Maria M. Vasilyeva

Saint Petersburg State Pediatric Medical University

Email: vas.maria.mikh.35@gmail.com
ORCID iD: 0009-0000-1190-7220
SPIN-code: 5080-4461
Russian Federation, Saint Petersburg

Alika A. Kulyova

N.N. Petrov National Medical Research Center of Oncology

Email: alika.abadzheva@yandex.ru
ORCID iD: 0000-0001-9886-1420
SPIN-code: 1038-8710
Russian Federation, Saint Petersburg

Olga E. Savyelyeva

Saint Petersburg State Pediatric Medical University

Email: olga_chechina@mail.ru
ORCID iD: 0000-0002-0301-8455
SPIN-code: 9633-9449

MD, PhD

Russian Federation, Saint Petersburg

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2. Fig. 1. Sphingolipid metabolism

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3. Fig. 2. Ganglioside biosynthesis by stepwise addition of monosaccharides to ceramide. The sequential action of the enzymes ST3Gal V (GM3 synthase), ST8Sia I (GD3 synthase), and ST8Sia V (GT3 synthase) creates precursors for the a, b, and c series gangliosides, respectively, while the 0 series gangliosides are directly derived from lactosylceramide. The ganglioside nomenclature follows Svennerholm's nomenclature.

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4. Fig. 3. Molecular structure of GD2 ((2S,4S,5R)-5-acetamido-6-[(1S,2R)-2-[(2S,4S,5R)-5-acetamido-2-carboxy-4-hydroxy-6-[(1R,2R)-1,2,3-trihydroxyprolyl]oxan-2-yl]oxy-1,3-dihydroprolyl]-2-[(2S,3R,4R,5S,6R)-2-[(2R,3S,4R,5R,6R)-4,5-dihydroxy-2-(hydroxymethyl)-6-[(2S,3 R)-3-hydroxy-2-[[(Z)-tetracos-15-enoyl]amino]octadecoxy]oxan-3-yl]oxy-5-[(2S,3R,4R,5R,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-(2-oxopropyl)oxan-2-yl]oxy-3-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-4-hydroxyoxane-2-carboxylic acid)

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5. Fig. 4. GD2 induction of phosphorylation of the hepatocyte growth factor receptor, FAK, and Lyn kinase and activation of the MEK/ERK, PI3K/Akt, and paxillin pathways. GD2 inhibits HGF-induced c-Met activation as well as cross-talk between c-Met and integrin, all effects inhibiting cascades mediated by FAK, Src family kinase, Ras, Raf, and mitogen-activated protein kinase (MAPK) involved in the control of cell adhesion, motility, and growth.

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