The growth of cancer demonstrates failure of the body's mechanisms to control interactions of some of its cells.  This could occur because the cancer cell does not respond to the control signals- whether due to damage to DNA, to presence of the products of the oncogenes, or to altered homeostatic control mechanisms.  A variety of different factors that can damage or change DNA in cells cause cancer, including viruses, many different chemicals and ultraviolet radiation.  Some rare forms of cancer exist also in those with an inherited deficiency in their ability to repair lesions in DNA.
     Most normal cells have differentiated, developing specific morphology and function.  Normal cells tend to lose their ability to proliferate during the process of differentiation.  In many tissues, the loss of mature cells is replaced by proliferation of less mature precursor cells followed by differentiation of their progeny.  Most cancers probably originate from these precursor cells. In cancer, cell proliferation usually continues even without a requirement for new cells, and differentiation is impaired.(9) (20)
 
 

    For tumor elimination to occur, the immune system must recognize the cancer cells as altered-self and act to destroy them, and the cancer cells must be susceptible to the killing.  First, lymphocytes must enter the tumor site.  CD4+ T-helper1 (Th1) lymphocytes can then recognize tumor-specific antigens in association with MHCII molecules on the surface of professional antigen-presenting cells and receive signals from costimulatory molecules such as B7.  Th1 lymphocytes should be activated and release appropriate cytokines including interleukin-2, interferon gamma, and tumor necrosis factor beta.  These cytokines and Class I MHC molecules with antigen-derived peptides on the surface of the cancer cells should be recognized by CD8+ Tcells in order to activate cytotoxic T lymphocytes (CTLs) that can lyse cancerous cells.  B lymphocytes may also be activated to secrete neutralizing antibodies that aid in cancer cell phagocytosis by antigen presenting cells, although their role in tumor immunity is less important.  Natural Killer (NK) cells and macrophage cells can also be involved in tumor destruction.  NK cells are not MHC restricted, so they can lyse many tumor cells by antibody-dependent cell-mediated cytotoxicity after they are activated by INFgamma.

    In healthy cells, cell growth is regulated by proto-oncogenes and tumor suppressor proteins.  Mutations caused by a variety of factors can stimulate the transformation of proto-oncogenes into oncogenes, resulting in the constant stimulation of the cell growth pathway, even in the absence of stimulating signals.

Some oncogenes are:
        c-myc- a gene for transcription factors that activate growth-promoting genes
        Bcl-1- a gene coding for a cyclin D1, a which stimulates the cell cycle clock
        Bcl-2 - a gene that codes for a protein that normally blocks apoptosis

Other mutations affect the availability of tumor suppressors which control the stimulatory signals necessary for cell growth.

Some tumor suppressing genes are:
        p53 - a nuclear protein gene coding for the p53 protein which can induce apoptosis
        VHL - a gene coding for a protein involved in renal cell cancer whose location is not yet clear (11)(12)
 
 

    Tumor elimination may not be effective if any of the processes necessary for induction of a cell-mediated response fail.  Cancer cells, therefore, evolve certain mechanisms to avoid the bodyís defenses.

    Tissue localization- since many tumor cells lack co-stimulatory properties, they can only be recognized in certain environments and in certain quantities.  If the cancerous cells are able to avoid lymphoid organs and develop into large tumors, it is difficult for the immune system to combat the tumor.

    Antigenic modulation- tumor cells can generate variants lacking tumor specific antigens on the cell surface that would mark them for destruction by Tcells and antibodies.  The tumor cells may also shed non-specifically immunosuppressive antigens into the sera in order to reduce immune response and induce tolerance to these antigens.

    Failure of lymphocyte response due to lack of adhesion molecules-  Lymphocytes normally migrate from the blood when adhesion receptors on the cells bind to certain ligands on target cells.  If the expression of these cellular adhesion molecules (CAMs) is repressed, the lymphocytes do not collect at the tumor site.

    Lack of costimulation- many tumor cells do not have the B7 protein on the surface, so the co-stimulatory signal necessary for T cell activation cannot take place.

    Release of immunosuppressive cytokines- secretion of low molecular weight proteins that induce inhibition of immune response down-regulates the destruction of cancer cells.  Some immunosuppressive cytokines secreted by cancer cells are transforming growth factor beta (TGF beta), interleukin-10 (IL-10) and vascular endothelial growth factor (VEGF)

    Downregulation of MHC I expression- CD8+ CTLs only recognize antigen associated with class I MHC molecules, so reduction of expressed level of MHC I molecules often allows tumor growth.

    Secretion of prostaglandins- tumor cells produce prostaglandins at increased levels when they interact with effector lymphocytes.  In vitro, prostaglandins have been shown to inhibit mitogenesis, cytolysis and antibody production.

    Interference of apoptotic pathways- expression of Fas-ligand causes lymphocytes bearing the Fas receptor to undergo apoptosis, preventing lymphocytes from destroying the tumor.  Other cancer cells express decoy Fas receptors that neutralize the Fas-ligand on lymphocytes.(12) (13) (14)