CANCER GLYCOME:CARBOHYDRATES AS

MEDIATERS OF METASTASIS

Submitted to:
Dr Hammad Ismael
Submitted by:
Maimoona Sajid
18191560-015
Biotech “B”
Biochemistry I
Main objectives

• Glycosylation and its types

• Carbohydrates and cancer
• Implementation of glycolysis in cellular metastasis
• Selectins and Cancer
• causes of altered glycosylation
• Therapy
GLYCOSYLATION

• Process by which reducing end of sugar covalently bind to lipid or

protein
• It is post-translational modification which results in the addition of
carbohydrate determinants, “glycans”, to cell surface proteins and
lipids.
• These glycan structures form the “glycome” and play an integral role
in cell–cell and cell–matrix interactions through modulation of
adhesion and cell trafficking.
• Glycosylation is increasingly recognized as a modulator of the
malignant phenotype of cancer cells
Types
O-linked glycosylation
 It is the attachment of a sugar molecule to the oxygen atom of serine (Ser) or
threonine (Thr) residues in a protein.
N-linked glycosylation
 It is the attachment of sugar molecule to a nitrogen atom of asparagine in a
process called N-glycosylation
Carbohydrates and Cancer

 Normal process of glycosylation is disrupted during malignant

transformation of cells
 These changes result in alterations in tumor cell surface glycans and
therefore interactions with endogenous lectins are impacted, which
influences the metastatic potential of the tumor cells
 Alterations in glycosylation of malignant cells can take a variety of
forms, including changes in the amount, linkage and acetylation of
sialic acids
 Changes in the branching of N-glycans mediated by
glycosyltransferases, alterations in expression of
glycosaminoglycans
Implementation of glycosylation in cellular
metastasis
 Adhesion molecules expressed on the surface of cancer cells play a crucial
role in metastasis
 Ability of cancer cells to metastasize is largely determined by their ability
to interact with endothelium, which is mediated, at the initial phases, by
integrins and selectins
Selectins

 Selectins are vascular cell adhesion molecules which mediate

adhesion of leukocytes and platelets with the endothelium.
P selectin
 P-selectin is present in the storage granules of platelets and
endothelial cells and rapidly translocate to the cell surface upon
activation
L selectin
 L-selectin is expressed on the surface of almost all leukocytes
Continued…….

E selectins
 It adheres the leucocytes to the capillary endothelium from where
they are extravasated
 L-Selectin mediates fast rolling of leukocytes on endothelium while
P- and E-selectin support the rolling at lower velocities
 The initial steps in cell migration involve tethering and rolling of
cells on the vascular endothelium
 This is mediated by the interaction of selectins on the endothelial
surface and their carbohydrate ligands
Selectins and Cancer
Selectins and cancer

• Selectin ligands consist of distinct glycan structures, which

incorporate the terminal core tetra saccharide structure SLex and SLea
on a protein backbone
• Presence of SLex and SLea leads to cancer
• sometimes, selectins are not functional due to altered glycosylation
which causes cancer
Causes of altered glycosylation

Hypoxia and glycan expression

 Under the poorly oxygenated conditions found in locally advanced
tumors, hypoxia-resistant cancer cells survive by acquiring hypoxia
tolerability through the HIF transcription factor
 Hypoxic culture of colon cancer cells induced a marked increase in
expression of selectin ligands
 SLex and SLea determinants at the cell surface, which led to a
definite increase in cancer cell adhesion to endothelial E-selectin
Continued…..

DNA Hyper or hypo methylation

 DNA methylation and histone deacetylation are mechanisms for suppression
of normal gene transcription commonly observed in cancers
 DNA hypomethylation leads to enhanced SLex production rendering colon
cancer cells more favorable to liver metastasis
 Change in cytosine methylation within the promoter of certain glycosylation
related genes is responsible for the expression of cancer-associated
carbohydrate antigens in gastrointestinal, colon, pancreatic, and breast cancer
 Therapy

 “Tumor markers” which are glycoproteins, have been analyzed for more
specific glycoforms to increase the sensitivity and specificity
 Aptamers are oligonucleotide-based recognition molecules that have
extraordinarily high sensitivity and selectivity towards their targets
 Aptamers are currently in clinical trials as potential anti-cancer agents, anti-
coagulants, anti-diabetic agents, and for treatment of macular degeneration
 Use of single lectins for specific detection of glycans associated with certain
malignancies has been helpful in application of concanavalin lectin and Wheat
germ agglutinin lectin (WGA) reactivity to p185 in breast cancer or the
measurement of T-antigen in cervical cancer using peanut agglutinin lectin