A 46-year-old woman is evaluated for a 2-month history of progressive abdominal distension, vague abdominal discomfort, and a bloating sensation. Physical examination shows moderate ascites. Laboratory evaluation reveals markedly elevated CA-125 and imaging studies show an ovarian mass. Molecular analysis of the malignant cells in ascitic fluid is performed, and these cells are found to have high telomerase activity. This enzyme promotes cell growth and malignancy by directly causing which of the following actions?

Question

A 46-year-old woman is evaluated for a 2-month history of progressive abdominal distension, vague abdominal discomfort, and a bloating sensation.  Physical examination shows moderate ascites.  Laboratory evaluation reveals markedly elevated CA-125 and imaging studies show an ovarian mass.  Molecular analysis of the malignant cells in ascitic fluid is performed, and these cells are found to have high telomerase activity.  This enzyme promotes cell growth and malignancy by directly causing which of the following actions?

Quizplus · Accepted Answer

Telomeres lie at the end of linear eukaryotic chromosomes and have tandem repeat DNA sequences, usually GT-rich repeats (eg, TTAGGG). They protect chromosomes from being recognized as damaged DNA, help to regulate gene expression, and participate in controlling cell replication and entry into senescence. As DNA polymerase cannot fully replicate the 3' end of the lagging chromosomal strands, cell division and aging lead to progressive DNA loss and telomere shortening at chromosomal ends. Once cells reach their maximum limit for proliferation (~50-70 divisions), the shortened telomeres trigger permanent growth arrest. Cell checkpoint genes (eg, TP53) become activated, and the critically short and dysfunctional telomeres lead to programmed cell death (apoptosis). Telomerase is an RNA-dependent DNA polymerase that consists of 2 molecules, human telomerase reverse transcriptase (TERT) and telomerase RNA (TR or TERC). Telomerase synthesizes telomeric DNA sequences that can replace the lost chromosomal ends of the telomeres. As a result, the telomere can divide without reaching a limit. Normal human cells have absent telomerase activity except in cells that need to divide regularly (eg, germ cells, certain adult stem cells). However, >90% of cancer cells contain increased telomerase activity, allowing for continued proliferation without apoptosis. (Choice A) Matrix metalloproteinases are proteases that degrade extracellular matrix proteins. They also modulate cell signaling by cleaving cell surface receptors, releasing apoptotic ligands, and inactivating chemokines/cytokines. These enzymes generally increase cell proliferation and allow for tissue invasion and metastasis. (Choice B) Proto-oncogenes often encode proteins involved in signal transduction in response to growth factors. Mutations in these genes can result in constitutive signal activation and increased transcription factor expression, stimulating cellular proliferation. (Choice D) Cyclin D is a protein that is synthesized during the G1 phase of the cell cycle and helps promote the G1/S phase transition. Increased expression of cyclin D can result in unchecked cellular proliferation. (Choice E) Vascular endothelial growth factor (VEGF) is a signal protein that helps create new blood vessels after injury. Cancer cells can overexpress VEGF to promote angiogenesis and allow for increased growth and metastasis. Educational objective: Telomerase is an RNA-dependent DNA polymerase that synthesizes telomeric DNA sequences that can replace the lost chromosomal ends of the telomeres. Cancer cells typically contain increased telomerase activity to allow for continued proliferation. __________ References: Progress in structural studies of telomerase. (http://www.ncbi.nlm.nih.gov/pubmed/24508601)

A 46-Year-Old Woman Is Evaluated for a 2-Month History of Progressive