Telomerase Activity in Prostatic and Renal Cell Carcinoma
Telomerase Activity in Prostatic and Renal Cell Carcinoma
By Hey Joo Kang, and David A. Corral, MD
The properties of telomeres and telomerase activity have been the target of intense clinical research since the association between the development of numerous tumor cell types and the degree of telomerase activity was first established in 1990.1 Since the introduction of the highly sensitive PCR-based TRAP assay, direct evaluation and measurements of telomerase activity in prostate and renal malignancies have been accomplished. Recent studies using this assay have found that teleromase activity is found in malignant prostate tissue but is absent in benign conditions such as benign prostatic hyperplasia (BPH) or normal prostate cells. Similarly, the high frequency of detection of telomerase activity in renal cell carcinoma and its absence in normal renal tissue suggests a possible role in tumorigenesis in this tissue type as well. These findings also have numerous implications for telomerase as a potential marker in the detection and monitoring of malignancies of the prostate and kidney.
Background
Telomeres are essential, non-coding units located at the 5’ terminal end of linear DNA in eukaryotic cells that stabilize the chromosomal ends during replication. These units consist of tandem repeats of the highly conserved G-rich sequence TTAGGG, and the cumulative length of these repeats are thought to be important in governing the lifespan of a cell. Normal human somatic cells lose 50-100 base pairs of terminal telomeric DNA with each round of replication. Thus, the presence of telomeres at the 5’ end act as a buffer zone preventing normal terminal chromosome shortening from reaching the coding regions of the genome. Telomerase is a ribonucleoprotein enzyme with reverse transcriptase activity that allows it to synthesize telomeric repeats onto chromosomal ends using a segment of its RNA component as a template.2 In the absence of telomerase activity, all telomeres would eventually shorten until a critical telomere length is reached, at which time cell senescence occurs. Since telomerase activity is directly involved in telomere maintenance, its activation in malignant cells may conceivably contribute to cell immortality.
Telomerase and Prostatic Malignancies
Prostate cancer is second only to lung cancer as the major cause of male cancer-related deaths in the United States and is the most common malignancy of older men today.3 Because multiple attempts at finding a consistent genetic change have yet to produce a readily identifiable marker for prostate cancer, it has become increasingly important to search for alternative means to determine the malignant potential of a suspicious lesion. Microscopic foci of prostate cancer are present in 40% of men older than age 50; however, most of these lesions will not progress but rather remain indolent in their clinical course. Finding a marker to distinguish which lesions will behave in a benign vs. malignant fashion over a patient’s lifetime would potentially save thousands of men from unnecessary treatment each year. By the same token, a marker that indicates a potential for progression can direct clinicians to treat individual patients in a more aggressive manner. The finding in recent studies of increased telomerase activity in primary prostate cancer raises the question of whether telomerase could serve as this marker.
The detection of telomerase activity by the highly sensitive TRAP assay in malignant prostate samples was first reported by Sommerfeld et al in 1996.4 His group demonstrated that 84% of pathologically confirmed prostate cancer was strongly positive for telomerase activity, whereas only 12% of samples of adjacent BPH tissue taken from the same prostates were weakly positive. The positive finding of telomerase activity in this 12% raises some important questions: were these samples, which were taken from matched areas adjacent to prostate cancer, positive due to small foci of contaminated prostate cancer within the specimen, or were they satellite metastases from the primary prostate cancer site? It is also notable that the remaining 14% of prostate cancer samples lacked telomerase activity. Whether these patients would experience a more indolent clinical course than those with tumors that do express telomerase will require further follow-up.
In samples taken from men with normal prostates or BPH only and no clinical or pathologic signs of cancer, there was no telomerase activity detected. The strong presence of telomerase activity in prostate cancer cells and the absence of telomerase activity in BPH samples and normal prostate tissue suggests the potential for telomerase as a cancer marker.
In normal nonmalignant cells, telomere shortening continues throughout the cell’s life span until a "crisis" phase is reached in which increased end-to-end chromosome fusion occurs and cell death results. During this phase, the average telomere length is very short or absent. Cells that are able to overcome this telomere crisis do so by adding short but stable telomere restriction fragments (TRFs) through the action of telomerase, theoretically allowing the production of immortal (i.e., malignant) clones. Because these stable TRFs are very short, it would be expected that overall telomere length in malignant cells would be actually shorter than those in nonmalignant cells destined for senescence and death, but whose telomeres have not yet been shortened by serial replication. This hypothesis was supported in the study by Sommerfeld and colleagues that demonstrated a progressive decline in TRF length from normal prostate, to BPH, and finally, to prostate cancer cells.4
The concept that the degree of telomerase activity correlates to histologic grade and, hence, prognosis of prostate cancer is under debate. A recent study by Lin et al revealed that the relative level of telomerase activity was directly associated with the degree of pathologic differentiation of the prostate cancer sample.5 When assayed by serial dilution, high levels of telomerase activity were consistently found in poorly differentiated prostate cancer, whereas only low levels were detected in well-differentiated samples. Samples of poorly differentiated prostate cancer still expressed telomerase activity after 100-fold dilution of cell extracts, while well-differentiated prostate cancer cells failed to maintain positive telomerase activity following a 10-fold dilution. These results were not reproducible in a study by Zhang et al; however, as the authors point out, this conflicting finding may be attributed to their small sample size (n = 101).6 (See Table.)
| Table | ||||
| Study (Ref #) | Malignant Cell Type | + Telomerase Activity | Telomere Length | Telomerase Activty Corresponding to Grade |
| Sommerfeld et al (Ref. 3) | prostate |
84% |
shortened |
N/S |
| Lin et al (Ref 4) | prostate |
90% |
shortened |
yes |
| Zhang et al (Ref 5) | prostate |
92% |
N/S |
no |
| Rhode et al (Ref 7) | renal cell |
74% |
shortened |
no |
| Mehle et al (Ref 6) | renal cell |
71% |
shortened |
no |
| N/S = Not studied | ||||
The strong correlation between prostate cancer and telomerase activity has multiple implications for its potential use as a tumor marker as well as a possible measure of histopathologic differentiation. Measurement of telomerase activity could provide critical prognostic information regarding the biological behavior of a tumor, which in turn affects the clinician’s management of the patient. Further study of this area is warranted.
Telomerase and Renal Cell Carcinoma
Renal Cell carcinoma (RCC) accounts for 90%-95% of malignant neoplasms arising from the kidney, and its refractoriness to various cytotoxic agents has been well documented. Because of the often cryptic clinical presentation of renal cell carcinoma, patients present to their physician late in the course of disease progression. At this time, no reliable tumor markers are available for the detection and monitoring of RCC.
Similar to prostate cancer, increased telomerase activity in RCC has been demonstrated using the TRAP assay in recent studies. The first, published in 1996 by Mehle et al, found 71% of renal cell carcinomas sampled were positive for telomerase activity.7 This finding was confirmed by Rhode et al whose study revealed a 74% correspondence rate.8 These findings suggest that telomerase activation early on in carcinogenesis is an important step in renal cell tumor progression. There is also a consistent relationship between TRFs found within malignant renal cells. It appears that malignant cells maintain their shortened telomere length through multiple cell cycles when compared to control samples which reach senescence following loss of the critical minimal telomere length. Conceivably, this could result from telomerase activation in the malignant cells which provide them with adequate tandem repeat fragments to achieve cell immortality and avoid cell death.
The heterogenous nature of renal cell carcincoma creates unique problems when studying the presence of telomerase activity directly or indirectly by studying TRF lengths. This heterogeneity may result in sampling errors which underestimate the true level of telomerase expression, activity, or TRF changes and may account for the relatively lower levels of telomerase detected in RCC compared to prostate cancer.
As described above for prostate cancer, a promising feature of telomerase detection is the correlation of strength of activity in dilutional assays with histopathological stage and grade.6 This has consistently been shown to be true in other malignancies such as neuroblastomas and gastric and breast cancers. In contrast to these malignancies, the potential use of telomerase activity as a prognostic tool has failed to be proven in studies of renal cell carcinoma.7,8 Although there is a wide varience from weak to strong telomerase activity among many renal cell carcinomas, there is no direct relationship between the degree of actvity and clinicopathologic parameters such as stage and grade. This implies that telomerase activity is unlikely to prove useful as a clinical predictor of a patient’s prognosis.
Conclusion
Telomeromase activation within prostate and renal cells appears to be a critical step in tumorgenesis, allowing the cell to achieve immortality and avoid cell senescence. The fact that non-malignant somatic cells lack telomerase activity adds credence to the importance of this enzyme in the pathophysiology of malignant cells. The utility of currently available tumor markers, such as prostate specific antigen, can be limited by their production by nonmalignant cells. The consistent results of telomerase activity in prostate and, to a lesser extent, renal cell carcinoma and its notable absence in BPH and normal cells make it a potentially useful diagnostic tumor marker. Further studies are needed to determine whether telomerase can also be used as a reliable indicator of clinical prognosis in prostate cancer. (Hey Joo Kang is a medical student at SUNY at Buffalo School of Medicine, Biomedical Sciences.)
References
1. Hastie ND, Dempster M, et al. Nature 1990;346:866-868.
2. Blackburn EH. Nature 1991;350:569-573.
3. Landis Sh, Murray T, Bolden S, et al. CA Cancer J Clin 1999;49:8-31.
4. Sommerfeld HJ, Meeker AK, Piatyszek MA, et al. Cancer Res 1996;56:218.
5. Lin Y, Uemura H, et al. J Urol 1997;157:1161-1165.
6. Zhang W, Kapusta L, Slingerland J, et al. Cancer Res 1998;58:619-621.
7. Mehle C, Piatyszek MA, Ljungberg B, et al. Oncogene 1996;13:161-166.
8. Rohde V, Sattler H, et al. Clin Can Res 1998;4:197-202.
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