How long are cancer cell telomeres

Telomerase hypothesis of cancer development: like the fuse on an explosive device

POLITICS: Medical Report

Cancer arises as a result of multiple changes in genes that control the growth and life program of cells. Since the natural aging process in individual cells is interrupted during tumor growth, analyzes of the molecular mechanism of aging appear to be particularly promising for cancer research. The "immortality enzyme" telomerase also plays a part in this concert; its increased activity is evident in most tumors and is viewed as a critical event for the sustained growth of most cancers.


Rapid advances in cell and molecular biology have set basic cancer research in motion. Knowledge of the molecular causes of most tumors is still very selective and speculative. But there are hopeful approaches to develop new perspectives for the prevention, diagnosis and therapy of malignant diseases from the knowledge about the life and aging process of cells. The telomere-telomerase hypothesis that Prof. Jerry W. Shay (University of Texas, Dallas) presented at the Bayer AG seminar "New Approaches to Cancer Therapy" in New York also belongs in this context.
Telomeres are repeating DNA sequences that are located at the end of the chromosomes (see Figure 1). It is currently believed that the telomeres have the task of regulating the frequency of mitosis in the cell. However, they pay a price for this impulse: the sequence of the telomeres is shortened with each cell division. If the chromosome ends consist of 15,000 base pairs of TTAGGG sequences at birth, the telomeres lose between 25 and 200 base pairs with each cell division. It goes without saying that this process cannot be repeated indefinitely: Once the telomeres have reached a critically short length, the cell ceases to divide and begins to age. "You can think of this as the fuse cord of an explosive device, which is getting shorter and shorter," said Shay.
For certain cell lines, however, nature has opposed this process. This is the enzyme telomerase, which is composed of both RNA and proteins. The telomerase uses its own RNA components as a template to synthesize the telomeres, i.e. the DNA base pairs TTAGGG. The job of telomerase is to protect the chromosomes from incomplete replication during cell division.
However, this is only the case with certain cell lines - and there to a different extent in each case: the greatest activity of telomerase is found in the germ cells; followed by the stem cells of those tissues that are constantly renewing themselves - such as the crypts of the gastrointestinal tract, the basal cells of the epidermis or the hematopoietic cells. Cell lines that lack telomerase lose their ability to divide after a certain time and have to age. Telomerase is therefore also known as the "immortality enzyme" and "stabilizer" of the telomeres.
However, the immortality enzyme can also be detected in most tumor cells. While telomerase works in healthy, proliferating cell lines for the benefit of the organism, its effect on tumors is reversed. By stabilizing the chromosomes of the tumor cells and thus maintaining the length of the telomeres, telomerase enables the cancer cells to divide and multiply endlessly. "Telomerase re-expression occurs in most tumors and is likely to be viewed as a critical event for the sustained growth of most cancers," reported Shay.
The activity of telomerase can be determined with the TRAP-eze®-kit - a test based on the polymerase chain reaction. Aspirates, ascites or frozen sections, among others, are suitable for the measurement. Over 4,000 patients with primary cancer have already been tested for telomerase activity using this method. Depending on the type of cancer, increased telomerase activity was found in 85 to 95 percent of the cases. For pancreatic cancer, 98 percent of the cases were positive (42 of 43 patients).
According to Shay, the telomerase test could even detect pre-cancerous changes (carcinomata in situ) in the lungs and breast. In contrast, all benign lesions were telomerase-negative. In situ hybridization has proven to be a new technique for detecting telomerase RNA.
"Our recent neuroblastoma studies show that tumors without telomerase activity stop growing," said Shay in New York. "We found telomerase activity in 94 out of 100 neuroblastoma cases - albeit to different degrees. In low-grade tumors (1 and 2), telomerase was only expressed to a low degree, and the children had a favorable course after surgery and chemotherapy. Children with higher-grade tumors Tumors (3 and 4) had a significantly poorer prognosis. "
In a special subgroup with advanced neuroblastoma (4s), in which spontaneous remission often occurs despite metastasis, the Texan working group made an astonishing observation: "In our study, three children in the 4s group had a spontaneous remission for which So far there has been no explanation at the molecular level. We could not detect any telomerase activity in any of them, ”explained Shay. These findings were recently confirmed by a working group from Los Angeles (C. P. Reynolds, Children's Hospital) - with the recommendation to use the telomerase test to assess the risk of 4s children.
Derived from these observations, the scientists aim to use drugs to inhibit the activity of telomerase in order to subject "immortal" cancer cells to the normal genetic pattern of aging and death. According to initial experience, short peptide nucleic acids are able to inhibit telomerase. "In further investigations, we introduced chromosomes from healthy cells into tumor cells and were able to determine that telomerase activity was suppressed - followed by a shortening of the telomeres and restoration of the cell aging process," says Shay (see Figure 2).
Dr. med. Vera Zylka-Menhorn

Telomerase hypothesis of cancer development: like the fuse on an explosive device

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