See also Cell Cycle Control
Introduction/Definitions:
Cancer involves a host of different pathogenic mechanisms which lead to cancer cells evading a host immune response. These mechanisms or abnormalities are important to note because they can serve as targets or various cancer therapeutic approaches. As with any disease whether cancer or a disease caused by bacteria, understanding pathogenic mechanisms can provide a rationale basis for any therapeutic plan of action.
Down-regulation of signals essential for the activation of immune cells: Tumor cells may down-regulate the expression of signals that are essential for the activation of host T cells. The mechanisms include defective expression of MHC Ags, absence of costimulatory or adhesion molecules, and alteration of Ag-processing or transport, resulting in an inability to present tumor-associated Ags. Strategies to augment the host immune response to tumor have included introduction of genes encoding MHC Ags, costimulatory molecules, or cytokines into tumor cells. The goal of these approoahces is to improve the immunogenicity and the Ag-presenting capability of tumor cells. Tumor cells have a lower capacity for antigen presentation, thus evading immune surveillance.
Overexpression of Complement Regulatory Proteins:
Juhl (J. Surgical Oncology 64: 222-230 (1997). show that virtually all of the cancer cell lines they studies for gastric, colon and pancreatic human cancer strongly expressed CD46, CD55 and CD59 and that in accordance with other studies expression fo CD55 and CD59 inhibited complement activaiton by mAbs, showing that complement resistance is a frequent even in gastrointestinal cancer limiting the potential of monoclonal antibodies.
CD59:
CD59 is highly expressed in many kinds of cancer cells as well as HIV that harvests CD59 from infected cells to escape antibody-mediated response. Young, (US 2006/0140963)
Extensive studies indicate that expression of CD59 results in lymphoma resitance to rituximab and HIV to antibody-mediated immune response. Therefore, it is imperative to develop a molecule capable of abrogating CD59 function. (Hu, “Domain 4 of ILY sensitizes antibody therapy on cancer and HIV through abrogating human CD59 function” FASEB J, 2008, 22 (meeting Abstract Supplement) 522. The chimeric mAb Rituximab is directed against the CD20 antigen and has been approved for use in treatment of non-Hodgkin’s lymphoma (NHL). Many patients that are CD20+ are unresponsive ot treatment and most patients who do resond will eventually develop resistance. In an effort to overcome this resistance, use of anti-CD59 antibodies to increasse CDCC has been investigated. Pre-incubation of one of the resistant cell lines with an anti-CD59 antibody sensitized the cells to treatment with Rituximab and human complement (Young, (US 2006/0140963, ¶11).
Complement is a main mediator for antibody mediated cancer cytolysis. Up-regulation and high expression of complement regulatory proteins such as CD59 can drive resistance to cancer therapy that activates complement as a component of its mechanisms of activity. An example of resistance mediated by CD59 overexpression is resistance to anti-CD30 chimeric MAB rituximab used for the treatment of B cell non-Hodgkin lymphoma (B-NHL). Qin US 13/391124. CD59 has been associated decreased sensitivity to therapeutic antibodies (WO/2008/1214202).
Hypermethylation:
Evidence supports that a relatively large number of cancers originate, not from mutations, but from inappropriate DNA methylation. In many cases, hyper-methylation of DNA incorrectly switches off critical genes, such as tumor suppressor genes or DNA repair genes, allowing cancers to develop and progress. This non-mutational process for controlling gene expression is described as epigenetics. As just one example, methylation of the promoter for a protein called ITIH5 has been shown to be associated with absence of the protein corresponding to downregulation of this gene in breast tumours (Veeck, Oncogene, 27, 2008, 27, 865-876)
Importance of Certain Cell Lineages:
It is known that the CD44+CD24-/low cell lineage population have the ability to form tumors when injected into immunodeficient mice. As few as 200 of these cells, termed “tumorigenic” cells, consistently formed tumors in mice. In constrast, the majority of the cancer cells in a tumor consist of “non-tumorigenic” cells with alternative pehnotypes. These cells failed to form tumors in NOD/SCID mice even when as many as 104 cells were injected (Al-Hajj et al., 2003).
Involvment of Hedgehog Pathway:
Many cancers ahve been shown to depend on the hedgehog pathway. It has been reported that activating hedgehog pathway mutations occur in sporadic basal cell carcinoma, primitive neuroectodermal tumors of the central nervous ystem and numerous other cancer types (WO 2012/006589).
Oncogenes and Proto-Oncogenes:
Oncogenes were discovered in virsues that cause cancer, the first being the Src gene, which is carried by the Rous sarcoma virus. When oncogenes are introduced into cells, they cause malignant transformation.
Proto-oncogenes are normal cellular genes that beocme oncogenic when mutatated. As only one allele needs to be mutated, these genes act in a genetically dominant fashion, and are gain -of-function mutations.
Cancer is a genetic disease in that it results from mutations in somatic cells. More than 100 genes have been identified as genes which are repeatedly altered in human cancer. These cancer critical genes can be groups into two classes according to whether the cancer risk arises from too much activity of the gene product or too little. Genes of the first class for which a gain of function mutation drives a cell toward cancer are called proto-oncogenes and their mutant overactive forms are termed “oncogenes.” Genes of the second class, for which a loss-of-function mutation creates the danger are called “.” A variety of oncogenes have been found to be amplified in human tumors (US 2004/0110197). For example, amplifcation of the Her-2 gene has been linked to breast cancer phenotypes (US 5,846,749).
Gain-of-function mutations or pro-oncogenes stimulate cells to increase their numbers when they should not. These mutations have a dominant effect. The types of genetic changes which can make a gene into an oncogene can be 1) point mutations, 2) partial deletions of sequences or 3) even by a chromosomal translocation that involves the breakage and rejoining of the DNA helix. These changes in turn can 1) occur in the protein coding region so as to yield a hyperactive product, 2) can occur in adjacent control regions so that the gene is simply expressed at higher concentrations or 3) can be due to extra copies of the gene due to gene amplification events caused by errors in DNA replication which also results in higher expression of the gene.
Tumor suppressor genes:
Tumor-suppressor genes are normal cellular genes that wehn mutated can lead to cancer, but in this case, both alleles must lose funciton to resutl in cancer. Tus, the genes act in a recessive fashion. The first tumor-suppressor gene was the retinoblastoma susceptibility gene (Rb), which predisposes individuals to a are form of cancer that affects the retina of the eye. The role of the Rb protin in the cell cycle is to integrate signals from growth factors. The Rb protin is called a “pocket protein” becasue it has binding pockets for other proteins. Its role is to bind important regulatory proteins and to prevent them from stimualting the production of cell-cycle-rleasing proteins such as cyclins or Cdks.
Point mutations in critical regions of tumor suppressor genes, such as p53, are often detected in tumor cells. When a tumor suppressor gene like p53 becomes mutation, cell proliferation accelerates in the absence of the suppressor. On the other hand, mutations in proto-oncogenes that transform them to active oncogenes, such as a mutant ras oncogene, produces cell proliferation caused by the presence of the mutant gene itself. The retinoblastoma tumor suppressor gene (Rb-1) is another extensively characterized tumor suppresor gene. Rb-1 plays an important role in cell cycle regulation. Altered or lost expression of the Rb protin is caused by inactivation of both gene alleles either through a point mutation or a chromosomal deletion. Rb-1 gene alterations have been found to be present not only in retinoblastomas but also in other malignancies such as osteosarcomas, small cell lung cancer and breat cancer.
Telomerase Dysfunctions:
There is evidence that the enzyme, telomerase, may provide one answer as to why certain cells turn cancerous. Most human cells seem to have a built-in limit to their proliferation. This replicative cell senescence is thought to be caused by changes in the structure of which are synthesized and maintained by a mechanisms that requires. In most human cells, other than those of the germ line and some stem cells, expression of the gene coding for the catalytic subunit of telomerase is switched off. As a result, the telomeres in these cells shorten with each round of cell division until eventually a danger signal is generated, arresting the cell cycle. This is not the case in most cancer cells which continue to express telomerase.
Impairment of Apoptotic Response:
The Bcl-2 protein plays a central role in determining whether or not cells will undergo apoptosis. The antiapoptotic functions of Bcl-2 are regulated by posttranslational modifications, including phosphorylation which determine whether Bcl-2 remains active or is targeted for degradation via the ubiquitin/proteasome system. Phosphorylation of specific amino acid residues of Bcl-2 has different functional consequences. For example, phosphorylation of the serine residue at Ser70 is required to its antiapoptotic function, whereas that of Ser87 appears to be responsible for its proteasome-dependent degradation. Several kinases are known to phosphorylate Bcl-2. Villar (Cancer Res 2009, 69(1), 2009) describe how PCPH protein confer resistance to cisplatin-induced apoptosis by inducing the phosphorylation of PKCalpha (a kinase) which in turn phosphorylates and stabilizes the antiapoptotic protein Bcl-2 by rendering it resistant to proteaseome-mediated degradation.
Release of Tumor derived vesicles:
Tumor cells have been shown to release membranous structures, termed “microvesicles” or exosomes” depending on size and composition. These cell derived vesicles can exhibit an array of proteins, lipids and nucleiv acids derived from the originating tumor. Tumor secreted exosomes have gained increased attention as a vehicle for intercellular communication with extensive auto-crine/paracrine functions. By exposing cell type specific adhesion receptors or ligands, exosomes can interact with specific cells and deliver their “signals” including bioacative , cytokines, growth factors, receptors and genetic materials (Taylor Analytical Biochemistry 428 (2012) 44-53).
Interaction of MSCs and tumor cells:
Evidence suggests that MSCs are potential precursors for tumor stroma and that MSCs within the tumor stroma are the promoters for breast tumor metastasis. In addition, MSCs may support tumor propagation or dissemination by preventing recognition of teh tumor cells from the immune system and promoting tumor cell invasiveness. Cho (Gynecologic Oncology, 123 (2011) 379-386