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Cancer The proliferation of normal cells is carefully regulated. However, such cells when exposed to chemical carcinogens, irradiation and certain viruses may undergo mutations leading to their transformation into cells that are capable of uncontrolled growth, producing a tumor or neoplasm. Benign: if it is not capable of indefinite growth and the host survives, which are self-limited, and do not invade or metastasize. Malignant if the tumor continues to grow indefinitely, metastasizes (spread to other locations in the body via lymph or blood), eventually killing the host. Most cancers form a tumor but some, like leukemia, do not. Cancer causes about 13% of all human deaths. Cancers can affect all animals. Oncology. The branch of medicine concerned with the study, diagnosis, treatment, and prevention of cancer. .
Classification Carcinoma: Malignant tumors derived from epithelial cells. This group represents the most common cancers, including the common forms of breast, prostate, lung and colon cancer. Sarcoma: Malignant tumors derived from connective tissue, or mesenchymal cells. Lymphoma and leukemia: Malignancies derived from hematopoietic cells. Germ cell tumor: Tumors derived from totipotent cells. In adults most often found in the testicle and ovary; in fetuses, babies, and young children most often found on the body midline, particularly at the tip of the tailbone; in horses most often found at the poll (base of the skull). Blastic tumor or blastoma: A tumor (usually malignant) which resembles an immature or embryonic tissue. Many of these tumors are most common in children.
Experimental Evidence for Tumor Antigens and Immunr Response 4. No tumor growth 2. Excise tumor 3. Re-challenge with same tumor 1. Inject Tumor 1. Inject Tumor 2. Excise tumor 3. Re-challenge with different tumor 4. Tumor grows
Biochemical properties of IDO • IDO is a monomeric protein containing heme and encoded by a gene over 15 kbp of DNA located on the short arm of chromosome 8 in humans and mice (Mellor AL et al., 2004). • The indoleamine 2,3-dioxygenase-like protein (INDOL1 or IDO2) gene was recently identified and found to locate adjacent to the IDO gene in mice and human (Ball HJ et al., 2007). • The signaling of IDO activation occurs mainly through (JAK-STAT) and (NF-κB) pathway (Mellor AL et al., 2004). • IDO might bridge between DCs and Tregs (Puccetti P et al., 2007).
IDO Molecular genetics and enzyme activity IDO transcription act through JAK–STAT signaling pathways on INF stimulatory response elements (ISREs) and γ-activating sequences (GAS) in the IDO promoter. Transcriptional repressor of IDO are not defined, cis and perhaps trans-regulatory factors are inferred. No specific post-translational modifications of IDO have yet been identified . Functional activity might also be regulated at the level of holoenzyme assembly (that is, incorporation of the haeme prosthetic group).
Essential amino acid deficiency antagonizes signalling through the mTOR (mammalian target of rapamycin) kinase pathway. mTORsignalling is required for normal initiation of ribosomal translation. This pathway is important for growth-factor signalling, and T cells are particularly sensitive to inhibitors of mTOR, such as the immunosuppressant drug rapamycin. A second amino-acid responsive pathway is initiated by the GCN2 kinase, which contains a binding domain that is specific for the uncharged form of transfer RNA (tRNA). Precisely how activating this stress-response pathway or inhibiting the mTOR pathway might affect the programme of T-cell activation is currently unknown.
Interactions between the tumour and cells of the immune system that foster an immunosuppressive microenvironment.
Inhibition of indoleamine 2,3‑dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy. (Muller, A. J et.al.2005) Nature Med. 11, 312–319
Substantial progress on all three issues has been made in the last 7 years.
