Tumors expressing a high level of certain types of
tumor-associated carbohydrate antigens (TACAs) exhibit greater
metastasis and progression than those expressing low level of TACAs, as reflected in decreased patient survival rate. Well-documented examples of such TACAs are: (i) H/Le(y)/Le(a) in primary
non-small cell lung carcinoma; (ii)
sialyl-Le(x) (
SLe(x)) and
sialyl-Le(a) (SLe(a)) in various types of
cancer; (iii) Tn and sialyl-Tn in colorectal, lung, breast, and many other
cancers; (iv) GM2, GD2, and GD3
gangliosides in
neuroectodermal tumors (
melanoma and
neuroblastoma); (v)
globo-H in breast, ovarian, and
prostate cancer; (vi)
disialylgalactosylgloboside in
renal cell carcinoma. Some glycosylations and TACAs suppress invasiveness and metastatic potential. Well-documented examples are: (i)
blood group A
antigen in primary lung
carcinoma; (ii) bisecting beta1 --> 4GlcNAc of N-linked structure in
melanoma and other
cancers; (iii) galactosylgloboside (GalGb4) in
seminoma. The biochemical mechanisms by which the above glycosylation changes promote or suppress
tumor metastasis and invasion are mostly unknown. A few exceptional cases in which we have some knowledge are: (i)
SLe(x) and SLe(a) function as
E-selectin epitopes promoting
tumor cell interaction with endothelial cells; (ii) some
tumor cells interact through binding of TACA to specific
proteins other than
selectin, or to specific
carbohydrate expressed on endothelial cells or other target cells (
carbohydrate-
carbohydrate interaction); (iii) functional modification of adhesive receptor (
integrin,
cadherin, CD44) by glycosylation. So far, a few successful cases of anti-
cancer vaccine in clinical trials have been reported, employing TACAs whose expression enhances
malignancy. Examples are STn for suppression of
breast cancer, GM2 and GD3 for
melanoma, and
globo-H for
prostate cancer.
Vaccine development canbe extended using other TACAs, with the following criteria for success: (i) the
antigen is expressed highly on
tumor cells; (ii) high antibody production depending on two factors: (a) clustering of
antigen used in
vaccine; (b) choice of appropriate
carrier protein or
lipid; (iii) high T cell response depending on choice of appropriate
carrier protein or
lipid; (iv) expression of the same
antigen in normal epithelial tissues (e.g., renal, intestinal, colorectal) may not pose a major obstacle, i.e., these tissues are not damaged during immune response. Idiotypic anti-
carbohydrate antibodies that mimic the surface profile of
carbohydrate antigens, when administered to patients, elicit anti-
carbohydrate antibody response, thus providing an effect similar to that of TACAs for suppression of
tumor progression. An extension of this idea is the use of
peptide mimetics of TACAs, based on phage display
random peptide library. Although examples are so far highly limited, use of such "mimotopes" as immunogens may overcome the weak immunogenicity of TACAs in general.