Telomerase and telomere length in the development and progression of premalignant lesions to colorectal cancer.
Telomerase and telomere length are increasingly studied as prognostic markers in malignancy. Telomerase is also known to be expressed in certain nonmalignant cells, although generally at low levels. We investigated telomerase activity and telomere length in premalignant, malignant, inflammatory, and normal colon specimens to determine whether significant differences exist and whether telomerase may serve as a marker for early- or late-stage colorectal cancer. Telomerase activity was evaluated in 130 frozen specimens from human colon cancer (n = 50), adjacent normal colon tissue (n = 50), colon polyps (n = 20), and colitis (n = 10) using a modified telomeric repeat amplification protocol assay, and telomere length was assessed by terminal restriction fragment analysis. High to moderate levels of telomerase activity were detected in 90% of colorectal tumors. Weakly positive activity was detected in 10%. None of the normal tissues exhibited telomerase activity. In polyps and colitis, telomerase activity was found in 60% (12 of 20) and 40% (4 of 10), respectively. Telomerase activity in both nonmalignant lesions was 25- to 54-fold lower than that detected in colon cancer (P < 0.001). We found a positive correlation between tumor cell infiltration determined in cryostat sections and telomerase activity (r = 0.886; P > 0.0001). Late-stage tumors (Dukes C + D) demonstrated increased telomerase activity compared to early-stage tumors (Dukes A + B). Telomere restriction fragments in colon tumors had peak values of 4.8 +/- 1 kbp that were significantly and consistently shorter than those of the adjacent normal tissues (7.54 +/- 1.3 kbp), polyps (7.5 +/- 0.7 kbp), and colitis specimens (7.7 +/- 0.5kbp; P < 0.0001). Telomeres were 0.6 kbp longer in tumors with high telomerase activity and in late-stage cancers (Dukes C + D) compared to those in tumors with low telomerase activity and in early-stage cancers (Dukes A + B). Our data demonstrate that telomerase in colon cancer was commonly acquired, and activity was higher than that in polyps and colitis. However, weak telomerase activity was detected in premalignant and inflammatory lesions. Telomeres in colon cancer were considerably shorter, an indication of extensive cell proliferation and population divisions, whereas adjacent normal colon specimens, polyps, and colitis had comparable telomere lengths. Our results indicate that increased telomerase activity occurs in colon cancer cells that have undergone extensive telomere shortening relative to surrounding normal tissues and in which telomerase-induced stabilization of telomeres may be critical for the continued proliferation of the malignant clone. The link between telomerase activity and stage suggests that telomerase is up-regulated as a function of increased tumor cell invasion, tumor progression, and metastatic potential in colon cancer.
Engelhardt
M
M
Rockefeller Research Laboratories and Surgery Department, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Drullinsky
P
P
Guillem
J
J
Moore
M A
MA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D003092:Colitis / Q000201:enzymology / Q000473:pathology; D003106:Colon / Q000201:enzymology / Q000473:pathology; D003110:Colonic Neoplasms / Q000201:enzymology / Q000473:pathology*; D003111:Colonic Polyps / Q000201:enzymology / Q000473:pathology*; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000473:pathology*; D017931:DNA Primers; D018450:Disease Progression; D005260:Female; D006801:Humans; D007413:Intestinal Mucosa / Q000201:enzymology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D011230:Precancerous Conditions / Q000201:enzymology / Q000473:pathology*; D012004:Rectal Neoplasms / Q000201:enzymology / Q000473:pathology*; D019098:Telomerase / Q000378:metabolism*; D016615:Telomere / Q000473:pathology*
D014408:Biomarkers, Tumor; D017931:DNA Primers; D019098:Telomerase