Ethan Nulton February 1, 12 Special Topic 4

Malignant cancer cells occur due to defects in DNA and protein synthesis. Often, purine nucleotides are uncontrollably replaced by another purine called an alpha mutation or a transition (or a pyrimidine with a different pyrimidine). Since purines have similar molecular structure, the resulting point mutation may not be deleterious. However, beta or transversion mutations, are much more significant and often result in an unintended protein. This is because a pyrimidine is replaced by a purine, or vice versa. Since this mutant protein, or amino acid sequence, differs from the desired protein the cell in which it was grown may identify it as non-self. For example, serological analysis of human melanoma cells displays different antigens on their structures than healthy skin cells (1). If this occurs, the cell may destroy the protein via proteasome degradation. Then the non-self amino acids derived from the mutant protein can then be presented on an MHC class 1 protein complex. CD8+ killer T-cells (CTLs) with the corresponding foreign amino acid sequence will then bind to the cell and destroy it (2). Also, many sick cells do not express MHC on their surface and Natural Killer cells (NK) destroy them (4). This is extremely important because if the DNA within the nucleus of the cell is compromised, then it will continually manufacture the wrong proteins, resulting in a tumor cell. Our cells are very altruistic, acting only for the benefit of the whole community.

Well if this is the case, then why am I an officer for Colleges against Cancer and Relay For Life? Shouldnt CTLs and NK cells eliminate every sick cancerous cell? Unfortunately there are data that show that many mutated amino acid epitopes are poorly immunogenic (1,4). In other words, they do not elicit a strong CTL or memory response. This may be due to the blocking of Tumor Necrosis Factor. Recent studies report that some tumor producing cells block or degrade TNF, an important cytokine involved in cytolysis of malignant cells (2). While it is evident that many cancerous cells avoid apoptosis or phagocytosis, studies have shown that immunocompromised individuals are at a significantly higher risk of having cancer (3). In fact, studies show that nude mice lacking NK cells, B cells and T cells have a higher incidence of cancer than their wild type companions (3). Critics of the cancer immunosurveillance concept argue that NK cells and CTLs destroying malignant cells are not the reason why cancer is more frequent in the immunocompromised but rather that the immune system just cleans up dead cells which also reduces tumorgenesis (3). But Robert Schreiber dismissed this by inserting tumors into transgenic mice. Subsequently, the tumors were rejected, suggesting that the immune system identified the cancerous antigens and destroyed them (3). In conclusion, it is undeniable that the immune system does not recognize every cancer cell as foreign and therefore cannot mount an effective defense. However, it is also evident that the immune system is a major line of defense from carcinoma because without the innate and adaptive immune system, cancer rates increase dramatically (3).

References Cited

1. Houghton, A. 1994. Cancer Antigens: immune recognition of self and altered self. Cornell University Medical College. 1-4. 2. Visser, K., Eichten, A., Coussens, L. 2006. Paradoxical roles of the immune system during cancer development. Nature. 6. 24-41. 3. Manjili, M. 2011. Revisiting cancer immunoediting by understanding cancer immune complexity. The Journal of Pathology. 224:1. 5-9 4. Smyth MJ, Thia KY, Street SE, et al. Differential tumor surveillance by natural killer (NK) and NKT cells. J Exp Med 2000; 191: 661668.