Cancer cells put on a life-threatening masquerade. They cloakthemselves in normalcy. They survive by not signaling their presenceto the body's immune system with alien proteins and/or foreigncarbohydrates. For the most part, they present the same molecularface that non-malignant cells present.
"It is really not a qualitative difference but a quantitative differencebetween normal cells and malignant cells," said Ralph Reisfeld, ofthe Scripps Research Institute, in La Jolla, Calif.
Today medical researchers are trying to exploit this quantitativedifference between normal and malignant cells by stimulating theimmune system to make antibodies to specific antigens that aboundon cancer cells. "Tumor vaccines" are being tested to bring theimmune response into the fight against cancer. Results of severalclinical trials have raised cautious optimism.
One promising trial makes use of antibodies directed against amolecule associated with melanoma cells.
"The data we have suggest that the antigen is a very useful target,"said Soldano Ferrone, professor and chairman of the Department ofMicrobiology and Immunobiology at the New York Medical College,in Valhalla, N.Y.
The target Ferrone and others are pointing the body's immunedefenses at is called melanoma-associated chondroitin sulfateproteoglycan (MCSP). Like its name, this molecule is big. It consistsof a 250 kDa glycoprotein and a 450+ kDa proteoglycan. This bigcell surface molecule has been implicated in many activities thatcontrol a cell's interaction with neighboring cells: cell growth, celladhesion, cell-substratum interactions and cell-cell contact. In acancer cell, this means MCSP could play a key role in the spread orprogression of the disease.
A problem for clinical researchers is that they did not know details ofthe structure of the antigen they were testing.
"As long as we don't have the detailed characterization of what weuse in patients, it is very difficult to target the therapy. Not knowingthe sequence, one cannot come up with improvements," Ferroneexplained
MCSP has a protein core and that is where the core of the target waslocated.
Proteoglycans are a large family of multifunctional molecules usuallyclassified as extracellular. They are versatile players in the playingfields around cells and in the spaces between them. But not too manyof these complex glycoproteins have been cloned and sequenced.
Some researchers think the side chains, the complex carbohydrates,are very important. But others believe that the research rewards lie inthe core because it is a protein.
Good News For Oncologists, Cancer Patients
The result is that there has been a lot of emphasis on the protein coreby scientists who believe that without knowing its structure, it isimpossible to correlate the structure of the molecule with its function,the holy grail of basic biological research.
This is why a report by Gerd Pluschke, et al., titled "Molecularcloning of a human melanoma-associated chondroitin sulfateproteoglycan," in the September issue of the Proceedings of theNational Academy of Science, is welcome news to oncologistworking in this area.
The authors cloned and sequenced the cDNA of the core protein ofhuman MCSP and, from the deduced amino acid sequence, theyalready have seen some clues about how the molecule mightcommunicate with its extracellular environment.
The amino acid sequence indicates that the core protein consists of ashort portion that resides inside the cell, a hydrophobic domain thatspans the cell membrane and a large extracellular portion.Furthermore, it suggests that the intracellular portion of the moleculehas three sites that might be phosphorylated. The addition ofphosphate, and the resulting conformational change in a protein'sshape, is a common means of passing signals from molecule tomolecule, cell to cell and system to system. Changes in the moleculeinduced by the addition or removal of a phosphate group couldmediate the interaction of MCSP with growth factors, for example.
Using probes prepared with the cDNA encoding the core protein, theresearchers found that a single species of RNA is present in humanmelanoma cell lines. Using a segment of the coding sequence and insitu hybridization techniques, they showed that mRNA for themolecule is present in human melanoma skin biopsy tissue. Strongindications for the presence of the molecule's RNA turned up inmelanoma cells but not in a variety of nonmalignant human and fetaltissues or in several leukemia and other cancer cell lines.
MCSP also is expressed, however, in sarcomas and brain tumors,according to protein chemist and a co-author Reisfeld, who said hebelieves MCSP could be a target as well as an initiator in futureclinical trials designed to recruit the immune system to fight cancer.
"In terms of a target, in clinical studies done at the National CancerInstitute, it has been shown that this antigen can be very well targetedby this antibody and has possible applications forradioimmunotherapy," Reisfeld said.
Knowing the amino acid sequence of the antigen may make it easierto improve approaches for exploiting MCSP as an antigen to elicitimmune responses in melanoma and other cancer patients.
"The work is very important because it provides the structuralcharacteristic for an antigen which is being used as a target forimmunotherapy," Ferrone said.
Furthermore, Ferrone added, "The authors have the opportunity toidentify the segments of the antigen which are immunogenic inpatients and which may be utilized to enhance the immunogenicity."
More On `How To Kill Metastasizes'
To grow and spread, tumor cells have to move.
"They can move in the bloodstream, of course. But to establish a newmalignant outpost, they have to adhere. They make use of everything,including cell adhesion molecules and growth factors. The more weknow about these processes of tumor cell adhesion, motility,spreading, formation of metastases, the better we can find usefulapproaches to kill metastasizes," Reisfeld said.
Reisfeld suggests that one could take fragments of this particularantigen and pulse them into the antibody-producing cells or eventransduce the cDNA into them. They then would be presented andproduce an immune response to the melanoma-associated antigen.
"If that were the case one could do this in cancer patients withmelanoma, glioma or sarcoma. Then the body's own defenses wouldreact against the tumor. That is what we all dream of. We should notjust say dream because there is already evidence that things like thiscan be done with particular peptides recognized by the immunecells," Reisfeld told BioWorld Today. n
-- Dean A. Haycock Special To BioWorld Today
(c) 1997 American Health Consultants. All rights reserved.