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Are CD46, CD55 and CD59 good targets for the treatment of malignant disease Essay Sample

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Are CD46, CD55 and CD59 good targets for the treatment of malignant disease Essay Sample

Clusters of differentiation which is often abbreviated to CDxx (xx representing a number specific to each CD molecule), is a naming system developed in 1982 to recognise surface molecules present on white blood cells that were recognised by monoclonal antibodies (Fiebig et al. , 1984). They can perform a number of functions such as acting as receptors or ligands and are usually involved in cell signalling, causing a cascade in certain immune responses. There are now over 250 proteins that are classified as CD molecules (Zola et al. , 2005).

This essay will look at three clusters of differentiation – CD46, CD55 and CD59 – known membrane proteins that protect against native complement damage (Xu et al, 2008) and conclude whether or not they are good targets in the treatment of malignant disease. CD46 (Membrane Cofactor Protein) is a type I membrane protein which acts as a complement receptor. It is a cofactor for the proteolysis of C3, so cells displaying CD46 will be protected from attack by the native complement system (Assem et al. , 2005). CD55, which is also known as Decay Accelerating Factor is also a membrane protein with a similar function to CD46.

CD55 causes a reversible reaction whereby it stops C3 convertases forming or accelerates the decay of convertase that has already formed. This prevents the formation of the membrane attack complex which is a group of four complement proteins (C5b, C6, C7 and C8) and many C9 molecules which form an open ended barrel like structure in the membrane of the target cell (this is essentially what destroys the cell) (Tschopp et al. , 1986). The third membrane CD protein is CD59 (also called protectin) interacts with the end molecules of the complement cascade – C8 and C9 – binding to C5b678 and preventing the binding and replication of C9.

Thus, the membrane attack complex (MAC) cannot form. These three proteins are thought to act together as an effective barrier to autologous complement damage (Simpson et al, 1997). As well as being a receptor for a particular strain of the measles virus and human herpes virus-6, CD46 has also shown to be present on malignant cells in higher concentrations than in normal cells. This goes some way to explaining why cancer cells can protect themselves from the complement system (Assem et al. , 2005).

Further studies on tumours have suggested that the expression of these three proteins may be different in tumours than to normal cells, and that they may play a role in tumour survival (Simpson et al, 1997). One study in particular, carried out by Simpson et al. , investigated cervical tissue – normal and cancerous – to compare whether the expression of complement regulatory proteins are in any way, linked to the maturation of malignant disease in the cervix.

They used monoclonal antibodies against each of the three complement regulatory proteins – BRIC 110, BRIC 216 and BRIC 220 and BRIC 300 against CD55 (DAF), BRIC 229 against CD59 and E4. and J4. 48 were the anti-CD46 (MCP) – to identify the levels of protein in the tissue. The investigation found that cells with CD55 were found concentrated at the centre of the tumour whereas areas of normal tissue were “randomly distributed” with CD55 (Simpson et al. , 1997). It appeared that the distribution of CD59 was broad in cervical tumours; however, some of the staining was described as “weak”, so there could have been a higher concentration of CD59 present. This study also carried out immunoblotting of the complement regulatory proteins.

In both the normal and tumour cells, a 70kDa CD55 product was observed, however in the tumour cells, a smaller CD55 protein was observed (between 54-56kDa). This lower mass CD55 molecule could be described as being from CD55+ tumour cells, or from CD55+ cells on the outside of the tumour. This would indicate that malignant cells have higher concentrations of these membrane bound complement regulatory proteins (mCRPs). This study concluded that malignant tumours arising from epithelial cells in the cervix always displayed heavy coverage of CD46 on the cell membranes.

It had been noted in past studies that this was also the case for carcinomas of the ovaries, colon and mammary glands (Simpson et al, 1997). It was reported in another study that higher concentrations of CD46 was found on leukemic white blood cells than on normal white blood cells. It suggested that CD46 may be important in the survival of malignant tumours (Seya et al, 1990). Although Simpson et al. reported higher levels of CD46 in tumour cells, CD55 coverage showed variability in the cervical cancer tissue. The actual tumour cells appeared to have no CD55 coverage apart from a few defined areas on the tissue.

This was also reported by Bjorge et al. (1997). Variation in the coverage of CD55 has also been described in skin carcinomas (Sayama et al. 1992). In contrast to this, a study by Cheung et al. (1988) observed that CD55 on carcinoma cells had an importance in the resistance to complement; however, Bjorge et al. found that the opposite was true for cervical carcinoma. In another study, CD55 and CD97 (a receptor of CD55) expression was increased in prostate cancer tissue compared to normal prostate tissue. It did not, however, record a significant difference in expression of CD46 and CD59 (Loberg et al. 005).

An investigation by Ravindranath and Shuler (Feb 2007) compared the coverage of the mCRPs on oral squamous cell carcinoma (OSCC) to breast carcinoma, pancreas carcinoma, colon carcinoma and melanoma. It found that OSCC and carcinomas of the breast and pancreas had the highest density of CD59, then CD55, then CD46. Melanoma showed a higher density of CD59, then CD46, then CD55, and carcinoma of the colon showed the CD46, then CD55, then CD59 (Ravindranath and Shuler, 2007). Taking into consideration all of the studies, there can be no firm conclusion drawn to the question posed by this essay.

It appears that all of the investigations looked at, concerning different types of cancers arrived at slightly different conclusions. Different types of cancers employ slightly different mechanisms in their protection against the complement system by expressing the membrane bound complement regulatory proteins in differing concentrations. What is without doubt, however, is that mCPRs do play a role in tumour cell survival, and that these may be a good target in the treatment of malignant disease, provided the treatment is differentiated according to the type of cancer that is being treated.

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