Chemistry Reference
In-Depth Information
studies on the mentioned epitopes (for details on their role in infl ammation and
on receptors of the selectin group of C-type lectins, please see Chapters 19 and
27.3; for structural details of a low-energy conformation of the sialyl-Lewis
x
tetra-
saccharide in complex with P-selectin, please see Figure 16.1h). With these two
classes of reagents listed in Table 25.1 at hand, the evidence from early biochemi-
cal analysis given above was confi rmed. Several aspects of glycan presentation in
tumors deviate from normal cells, among them relatively increased degrees of
branching and sialylation of
N
- glycans, enhanced presentation of short - chain
mucin - type
O
-glycans with sialylation, and alterations in the abundance of histo-
blood group AB0 and Lewis epitopes (for details on these structures, please see
Chapters 1, 7 and 27) [4, 5]. The nature of these changes can vary with the tumor
type so that the detected malignancy-associated deviations from controls should
always be interpreted in the context of the analyzed tumor histology and never be
extrapolated to other tumor classes.
At the molecular level, the discovery of oncogenes afforded the opportunity to
further test the hypothesis that there is a connection between factors causing
malignancy and glycosylation. Transforming cells with oncogenes should then
induce aberrant glycan production. Indeed, this was the case, and a connection
between oncogenes such as
ras
or
src
and transcriptional regulation of glycosyl-
transferases, especially
N
- acetylglucosaminyltransferase - V responsible for adding
the
2,6 - sialyltransferase - I adding
sialic acid to branch ends (for details on
N
-glycan structure, please see Chapters
6 and 8, on KO models in Tables 23.1 and 27.4), was inferred to underlie increases
in the respective substitutions [4, 5]. While surely contributing in a valuable
manner to histopathological characterization and even delivering prognostic
assessments in certain cases, the quest for a truly tumor- specifi c carbohydrate
marker still continues. However, this search must not necessarily be successful to
prove the importance of tumor cell glycosylation. Already quantitative changes in
a few key aspects of global glycosylation may be able to make their presence felt
as biologically potent features of the malignant phenotype. Moving from initial
detection of glycome differences to ascribing functional relevance guides us from
the past to the present. By doing so we will encounter two main routes glycans
can take to exert an infl uence on cell properties.
β
1,6 - branch to complex - type
N
- glycans and
α
25.2
The Present
The fi rst mode by which tumor-associated glycans can have an impact on the
establishment of the malignant phenotype is by modulating the functionality of
the protein part of a glycoprotein. Evidently, if altered glycosylation shifts the dis-
tribution of charge, sialylation being a major factor, and conformational prefer-
ences of glycan chains (for details on modeling glycan parameters and the role of
substitutions in the
N
-glycan core as modulators of conformational preferences,
please see Chapter 2), cell surface glycoproteins such as integrins or growth factor
