Immune markers in progression of colorectal cancer
Cancer growth and spread is controlled by tumor microenvironment, which is composed of immune and other cell types. Recently, a survival prediction tool, the immunoscore, was introduced for colorectal cancer (CRC), based on quantification of two tumor suppressive immune T cells (CD3+ and CD8+) in the primary tumor. The immunoscore was shown to provide a better prognostic prediction than the traditional TNM classification. The aim of the project is to reconsider the use of tumor microenvironment in the assessment of CRC prognosis and it will also include metastatic patients in the development of a prognostic tool, based on cellular composition of 11 cell types. The sample set available to this study is internationally unique, including over 100 patients for whom samples of normal colonic mucosa, primary tumor and metastasis will be obtained. Among the identified patients, half presents with liver metastases at diagnosis (stage IV) while the other half develops metastases up to years later (stages II/III).
Telomere dysfunction in progression to colorectal cancer
Telomeres are the TTAGGG nucleotide repeat sequences located at the termini of linear human chromosomes about 10-15 kb long. Due to limitations of semiconservative eukaryotic DNA replication machinery, telomere repeats shorten with successive mitotic cell divisions. The shortening can be overcome by the telomerase enzyme adding repetitive nucleotide sequences to the ends of chromosomes. Shortening of telomeres ultimately results in replicative senescence and blocking of cell division, which prevents ultimate fusion of short chromosomal ends and ensuing genomic instability. Telomerase is reactivated in over 90% of human cancers, which is one telomerase-related mechanism of promoting cancer progression. Telomere length determination has been of considerable clinical interest when measured both in tumors and blood cells. Telomere length in tumors, despite telomerase reactivation, is usually shorter than that in cells of the surrounding tissue. The reason is believed to be the higher division rate of tumor cells, which is not fully compensated by telomerase activation. The project will involve measurement of telomere lengths in colorectal cancer in order to test for differences in telomere length between tumors and the adjacent mucosa and between tumors located at different sites were associated with patient survival.