Molecular BIology of Cancer Topics
Human tumors arise form a single transformed cell. Given the odds of a single transformed cell to develop into cancer explains why this is usually a disease of old age. Particular types of tumors will have specific chromosomal rearrangments, for example the Philadelphia chromosome in chronic myelogenous leukemia and common immunoglobin expresion in B-cell lymphomas.
Analysis of X-linked gene expression in females is used to study the clonality of tumors. Females have random inactivation of an X-chromosome during development. Since individual cells will express only the isoenzyme coded by the active X-gene, subjects that are heterozygous for an X-linked enzyme have normal tissue that produce either enzyme. A tumor originating in a single cell will produce only one isoenzyme, whereas a tumor of multicellular origin will produce both types. All human tumors observed are homologous for the enzyme, i.e. produce only one isoenzyme.
A tumor arises from a single cell transformed as a result of a genetic mutation. All the cells of the tumor will have the same mutation. Still, secondary genetic changes may occur in subclones of the original transformed cell, thus adding additional mutations to part of the tumor. As a result, there is genetic heterogenicity in a tumor developed from a single transformed cell, while all the cells in the tumor still contain the original transforming mutation. The final cancerous state results from multiple genetic changes that occur over many years. Unfortunatelly, cancer can be detected only at late stages in disease development, when the tumor has adquired more genetic diversity.
The genetic changes that results in cancer allow the transformed cells to have limitless replicative potential. These changes are illustrated by the main differences between non-malignant and malignant cells regarding growth control, mobility, karyotype and antigeneicity, as seen in culture. While normal cell groth in vitro will stop as cells come in contact to one another, malignant cels are able to grow beyond and over their neighbors, forming foci. Normal cells require growth factors to survive while malignant cells do not. Normal cells will undergo scenecense and die off after a few generations of growth in vitro, but malignant cells will not, thus having an infinite lifespan. While normal cells need some kind of rigid attachement matr5ix to grow, malignant cells do not, and will even grow in soft agar. Malignant cells have a wrong number and/or size of chromosomes (abnormal karyotype). They are also sensitive to immune responses, thus will sometimes only form tumors in athymic mice.
Telomerase
Human telomerase consists of repeats of the srquence TTAGG/CCTAA at the ends of chromosomes. Telomerase is a ribonucleotide enzyme that synthesizes telomeric sequences. This enzyme is active only in germline cells and allows for telomeres 15 kbp in length. In somatic cells, telomerase is inactive and telomeres are < 15 kbp. Telomerase is a ribonucleoprotein composed of an RNA subunit (hTR) and a catalytic subunit (hTERT). The RNA subunit serves as a template with a sequence complimentary to the telomerase sequence.
According to the telomere hypothesis, telomers get shorter withe ach round of somatic cell division. Scenecense occurs when telomers shorten to a critical threshold length. Telomeres normally shorten during semiconservative DNA replication due to the removal of the RNA primer from the endding of the "lagging" strand. This leaves a gap at the end of one of the two newly synthesized chromosomes.
Telomerase is associated with cell inmortalization and its activity is present in human tumor tissue but not in normal tissue. In a few transformed cells, telomerase is on, for example HT1299 human colon carcinoma cells. Stable transfection of normal human cells with telomerase results in longer telomeres and no senecence. Most malignant colon cancers have telomerrase activity. Suppression of telomerase activity in tumor cells blocks tumor growth. Expression of a mutant telomerase in ovarian cancer cells eliminates tumorigenicity in vivo, after injecting athymic mice, compared to wild-type cancer cells.
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