Telomerase Appears to Play a Role in Cancer Cell Immortality

TORONTO, Canada--Understanding why normal cells grow old and diewhile cancer cells do not could be a boon to cancer research (seedrawing on page 1). US and Canadian scientists have discoveredthat a protein called telo-merase may be the cause of the "eternalyouth" of cancer cells, and they are seeking to develop drugsto block its effects.

Researchers have found that significant levels of telomerase arepresent in as many as 95% of all malignant cancer cells in humans,but not in normal tissues, with the exception of reproductivecells from ovaries or testes.

In a presentation at the American Association for Cancer Researchmeeting, Jerry W. Shay, PhD, a cell biologist at the Universityof Texas Southwestern Medical Center at Dallas, said that telomerasemay be the substance that gives cancer cells their immortality,and if there is no telomerase activity in tumors, those tumorsmay spontaneously regress.

In his study on neuroblastoma tumors, the most common solid tumorfound in children under the age of 5, Dr. Shay and his team foundtelomerase in 94 of 100 tumors.

The tumors with high levels of telomerase activity also had othergenetic changes and an unfavorable prognosis. The tumors withlow telomerase activity did not have genetic mutations and wereassociated with a favorable prognosis.

Three of the neuroblastoma tumors that did not show telomeraseactivity were from a type of tumor that often spontaneously regressesin children.

The investigators made similar observations in small-cell lungcancer, with 100% of samples studied testing positive for telomerase.In contrast, only about 80% of 136 non-small-cell lung cancersexpressed telomerase, Dr. Shay said. "This may explain whyso many more non-small-cell lung cancer patients respond wellto treatment."

Telomerase Blocker in the Future?

Biochemist Calvin B. Harley, PhD, of Geron Corporation, MenloPark, Calif, and his colleague Dr. Silvia Bacchetti, a molecularbiologist at McMaster University, Hamilton, Canada, believe thattelomerase could prove to be a universal target in tumorigenesis.

Dr. Harley and other researchers at Geron are working to developa drug to block telomerase. Their hope is that the agent willprevent cancer cells from maintaining their telomeres (the endsof chromosomes, see below) and, as a result, stop multiplyingand eventually die.

By limiting the growth of cancer cells, the effectiveness of otheranticancer drugs might also be enhanced, Dr. Harley said at amedia conference held in conjunction with the meeting.

Both Dr. Shay and Dr. Harley hope that any agents developed toblock telomerase will affect only telomerase and not produce adverseeffects in patients. Such an agent could be a universal treatmentfor cancer, Dr. Harley said.

Telomeres and Their 'Repairman'

When chromosomes replicate in preparation for cell division, theends of the chromosomes, known as telomeres, become a bit shorter.After several dozen generations of cell division, the telomeres,which are made up of short, repeated DNA sequences, have becomeso small that the cells lose their ability to divide, and theyget old and die.

In his talk at the AACR, Dr. Shay said that for reasons that arenot yet known, normal cells do not compensate for the gradualdeterioration of telomeres, but cancer cells do. The high levelsof telomerase found in cancer cells suggest that the enzyme playsan important role.

When telomerase is present, it acts like a molecular repairman,fixing and maintaining the telomeres so that they never drop belowthe critical length. As a result, the cells can keep on dividingforever.