Targeting cancer-associated glycans as a therapeutic strategy in leukemia

Figures & data

Table 1. Structure and classification of glycans.

Types	Sub-types	Forms	Groups	Subgroups
Glycoconjugates	Conjugated to proteins	Glycoproteins	N-linked
			O-linked
			GPI-linked
		Proteoglycans
	Conjugated to lipids	Glycolipids	GSLs	Neutral (non-sialylated) GSLs	The ganglio- and isoganglio
					The lacto- and neolacto-
					The globo- and isoglobo-series
				Acidic (sialylated) GSLs	Gangliosides
			Glycoglycerolipids
			GPI
Unconjugated		GAGs	Heparin/heparan sulfate
			Chondroitin sulfate/dermatan sulfate
			Keratan sulfate
			Hyaluronic acid (hyaluronan)

GPI, Glycophosphatidyl inositol; GSLs, Glycosphingolipids; GAGs, glycosaminoglycans.

Table 2. Serum/plasma glycans and glycoproteins as cancer biomarkers.

Biomarker	Known as	Type of cancer	Citation(s)
CA19–9	sLeA	Pancreatic cancer	Ballehaninna and Chamberlain (2012)
α2–3-sialylated PSA		Prostate cancer	Zhang et al. (2018)
CA125	MUC16	Ovarian cancer	Charkhchi et al. (2020)
CA 15-3	MUC1	Breast cancer	Duffy et al. (2000)
CEA		Colorectal, Bladder, Breast, Pancreatic and Lung cancer	Kailemia et al. (2017)
CA72-4		Gastric cancer	Xu et al. (2021)
CA27-29		Breast cancer	Gion et al. (2001), Rack et al. (2016)
Anti-Neu5Gc antibodies		Breast cancer	Blsakova et al. (2019)
Neu5Gc	xeno-autoantigen	Breast cancer	Shewell et al. (2021)
		Colorectal cancer	Higashi et al. (1985), Kawai et al. (1991)
		Liver cancer	Koda et al. (2003)
		Ovarian cancer	Diaz et al. (2009)
sLeX		Pancreatic, Lung, and Gastric cancer	Lan et al. (2016), Ferens-Sieczkowska et al. (2013)
sTn antigen	CD175s	Mucinous carcinoma	Nakagoe et al. (2001)

sLeA, sialyl Lewis(A); PSA, prostate-specific antigen; MUC, Mucin; CEA, Carcinoembryonic antigen; Neu5Gc, N-glycolyl-neuraminic acid; sLeX, sialyl Lewis(X); sTn, sialylated Tn antigen.

Table 3. Examples of TACA overexpressed due to upregulation of sialyltransferases and fucosyltransferases.

Enzyme family	Enzyme	TACA	Cancer type	Citation(s)
Fucosyltransferases	FUT8	N-linked glycans	Hepatocellular carcinoma	Wang et al. (2015a)
		N-linked glycans	NSCL^a, liver, ovarian, thyroid, and colorectal cancers	Chen et al. (2013)
	FUT3	sLeX and sLeA^b	Pancreatic cancer	Zhan et al. (2018)
	FUT7	sLeX	Adult T cell leukemia cells	Hiraiwa et al. (2003)
	FUT4	LeY^c	Breast cancer	Yan et al. (2015)
	FUT6	sLeX	Breast cancer	Matsuura et al. (1998)
Sialyltransferases	ST3GAL5^d and ST6GAL 1	GM3	Pediatric acute lymphoblastic leukemia	Mondal et al. (2010)
	ST6GAL1	α2,6-linked sialic acid in N-glycans	Pancreatic and colon cancers	Reily et al. (2019)
			Rectal adenocarcinomas	Smithson et al. (2022)
	ST3GAL4	sLeX	Gastric cancer cells	Gomes et al. (2013)
		sLeX and sLeA	Colorectal cancer	Kudo et al. (1998)
		Sialylated N-glycans	Chronic myeloid leukemia^e	Zhou et al. (2017)
	ST3GAL5 and ST8SIA4	Sialylated N-glycans	MDR acute myeloid leukemia^f	Ma et al. (2015)
	ST3GAL3	sLeX	Ovarian cancer^g	Huang et al. (2009)
	ST6GalNAc I	Sialyl-Tn O-glycans	Chronic myeloid leukemia	Sewell et al. (2006)
	ST6GalNAc IV	Sialyl-T antigen	Leukemia cell lines	Yamada et al. (2012)

^a NSCLC, non-small-cell lung cancer.

^b sLeX, sialyl Lewis(X); sLeA, sialyl Lewis(A).

^c LeY, Lewis Y.

^d ST3GAL5 (GM3 synthase), catalyzes α2-3-sialylation of lactosylceramide (LacCer) with resulting ganglioside GM3. It is predominantly expressed in childhood acute lymphoblastic leukemia.

^e Elevated ST3Gal4 in chronic myeloid leukemia (CML) cells is associated with imatinib resistance.

^f Classic Multidrug resistance (MDR) is the consequence of overexpression of transporter proteins, for example, P-glycoprotein (P-gp) and MDR-related protein 1 (MRP1), belonging to the ATP-binding cassette family, which lead to lower intracellular drug accumulation and thus reduce cellular toxicity of chemotherapeutic agents.

^g High level of ST3Gal III produces cellular resistance to Taxol and thus reduced the efficacy of Taxol therapy in ovarian cancer cells.

Figure 1. Cancer-associated glycans/tumor-associated carbohydrate antigens (TACAs). TF, the disaccharide Thomsen-Friedenreich antigen; Tn, the monosaccharide Thomsen-nouvelle antigen; sTF, sialylated TF antigen; sTn, sialylated Tn antigen; SSEA-1, stage-specific embryonic antigen-1.

Table 4. Selected cancer associated-glycans expressed in several types of human cancers.

TACA	Clinical application(s)	Citation(s)
TF antigen (CD176)	CD176 is a promising target for immunotherapy since it is exclusively expressed at the surface of human leukemic cells. Anti-CD176 antibody can induce tumor-specific apoptosis of CD176-positive leukemic cells	Yi et al. (2011)
Tn antigen (GalNAc;CD175)	Engineered anti-Tn-MUC1 CAR T-cells eradicated leukemia and pancreatic cancer in mice	Posey et al. (2016)
	Strongly expressed in CLL	Aller et al. (1996)
sTn antigen (CD175s)	sTn constitutes a pan-carcinoma antigen associated with adverse outcome. Lessons learnt from failure of the anti-STn vaccine, Theratope, would revive the pursuit of successful anti-STn immunotherapy	Julien et al. (2012)
N-glycans	An increased relative abundance of high-mannose type N-glycans was found to be associated with morphological progression of MLS	Heijs et al. (2020)
Fucosyl Gb5 (Globo H)	Globo-H is a potential tumor-associated antigen on prostate and breast cancer cells	Bremer et al. (1984)
Sialyl-Gb5 (SSEA4)	A potential therapeutic target in astrocytoma	Lou et al. (2014)
Gb3 (the CD77 antigen)	CD77, a B cell-associated antigen, is characterized by its specific expression on germinal center B cells and is a marker of Burkitt lymphoma	Schwartz-Albiez et al. (1990), Mangeney et al. (1991), Mangeney et al. (1993)
	Breast cancer and lymph node metastases	LaCasse et al. (1999), Stimmer et al. (2014)
	Ovarian cancer	Jacob et al. (2012)
	Colorectal cancer	Kovbasnjuk et al. (2005)
	Pancreatic cancer	Maak et al. (2011)
Gg3	Marker of Hodgkin lymphoma	Kniep et al. (1983)
GD2	A tumor-specific marker for neuroblastoma, and antibodies against it are currently part of maintenance therapy for this pediatric malignancy	Ploessl et al. (2016)
	Glioma	Mujoo et al. (1987)
	Melanoma	Morton and Barth (1996)
	SCLC	Yoshida et al. (2001), Yoshida et al. (2002)
9-O-Ac-GD2	Neuroblastoma, SCLC, melanoma, and renal carcinoma	Alvarez-Rueda et al. (2011)
	Breast cancer	Cavdarli et al. (2019), Cavdarli et al. (2021)
GD3	The ganglioside GD3 and its 9-O-acetylated form (9-O-Ac-GD3, also called CD60b) are sialylated glycolipids expressed in glioblastomas and melanomas	Yeh et al. (2016), Pukel et al. (1982), Scott et al. (2001)
	T-ALL	Yamashiro et al. (1993)
9-O-Ac-GD3	Breast cancer	Marquina et al. (1996)
	Basal cell carcinomas	Fahr and Schauer (2001)
	Tumors of neuroectodermal origin	Kohla et al. (2002)
	Childhood ALL	Mukherjee et al. (2008)
	Glioblastoma	Birks et al. (2011)
Fuc-GM1	A potential target for therapeutic approaches in small cell lung cancer (SCLC)	Ponath et al. (2018)
GM2	T-ALL	Okada et al. (1996)
	Renal carcinoma	Kudo et al. (2003)
GM3	NSCLC	van Cruijsen et al. (2009)
	GM3 was found to induce monocytic differentiation in leukemia cells	Nakamura et al. (1989)
Neu5GcGM3	The anti-idiotype mAb against NeuGcGM3 (racotumomab) conferred a significant survival advantage in NSCLC	Alfonso et al. (2014)
	Cancer vaccine for advanced breast cancer	Carr et al. (2003)
LeY	A carbohydrate antigen over-expressed by malignant myeloid cells	Buckley and Walter (2015)

TACA, tumor-associated carbohydrate antigen; TF, the disaccharide Thomsen-Friedenreich antigen; Tn, the monosaccharide Thomsen-nouvelle antigen; sTn, sialylated Tn antigen; GalNAc, N-acetyl-galactosamine; MUC1, Mucin1 (CD227); CAR-T cells, chimeric antigen receptor (CAR)-T cells; CLL, chronic lymphocytic leukemia; MLS, Myxoid liposarcoma; SSEA, stage-specific embryonic antigen; GSLs, glycosphingolipids; ALL, acute lymphoblastic leukemia; SCLC, small cell lung cancer; NSCLC, non-small-cell lung cancer; 9-O-Ac, 9-O-Acetylated; Fuc, fucose; Fuc-GM1, Fucosyl-GM1; Neu5GcGM3, GM3 containing the non-human sialic acid N-glycolyl-neuraminic acid (Neu5Gc).

Figure 2. The effect of P-selectin antagonism. The upregulation of P-selectin on tumor associated vasculature (in contrast to E-selectin) may be less about induction of survival and regeneration of malignant cells but more as a factor directly contributing to metastatic cell homing. The simultaneous increased expression of P-selectin on endothelial cells induced by inflammatory cytokines in conjunction with increased expression of P-selectin ligands induced by aberrant glycosylation renders them hyperadhesive. By blocking P-selectin ligands, engineered lectins or glycomimetics can relocate AML leukemic stem cells (LSCs) to the peripheral blood followed by their elimination by chemotherapy. Thereferofer, P-selectin blockade can predictably prevent therapy resistance.

Figure 3. The lectin-protease conjugate. Binding of a lectin-protease conjugate to membrane glycans activates the lectin pathway in a manner similar to the classic pathway where cleaving both C4 and C2 generates the C3 convertase (C4b2a). The C3 convertase cleaves C3 to give rise to a smaller C3a fragment and a larger C3b fragment. The C3b molecules associate with C4bC2a or C3bBb complexes to form the C5 convertase (not shown). The C5 convertase cleaves C5 and initiates activation and assembly of the terminal components, C5, C6, C7, C8, and C9, into the C_5b-9 membrane attack complex (MAC) on the surface of target cells.

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Data availability statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.