Abstract
Colorectal cancer (CRC) is one of the most common cancers in the Western world. 5-Fluorouracil (5FU)-based chemotherapy (CT) remains the mainstay treatment of CRC in the advanced setting, and activates executioner caspases in target cells. Executioner caspases are key proteins involved in cell disassembly during apoptosis. Activation of executioner caspases also has a role in tissue regeneration and repopulation by stimulating signal transduction and cell proliferation in neighbouring, non-apoptotic cells as reported recently. Tissue microarrays (TMAs) consisting of tumour tissue from 93 stage II and III colon cancer patients were analysed by immunohistochemistry. Surprisingly, patients with low levels of active Caspase-3 had an increased disease-free survival time. This was particularly pronounced in patients who received 5FU-based adjuvant CT. In line with this observation, lower serum levels of active Caspase-3 were found in patients with metastasised CRC who revealed stable disease or tumour regression compared with those with disease progression. The role of Caspase-3 in treatment responses was explored further in primary human tumour explant cultures from fresh patient tumour tissue. Exposure of explant cultures to 5FU-based CT increased the percentage of cells positive for active Caspase-3 and Terminal Deoxynucleotidyl Transferase dUTP Nick end Labelling (TUNEL), but also the expression of regeneration and proliferation markers β-Catenin and Ki-67, as well as cyclooxygenase-2 (COX-2). Of note, selective inhibition of Caspase-3 with Ac-DNLD-CHO, a selective, reversible inhibitor of Caspase-3, significantly reduced the expression of proliferation markers as well as COX-2. Inhibition of COX-2 with aspirin or celecoxib did not affect Caspase-3 levels but also reduced Ki-67 and β-Catenin levels, suggesting that Caspase-3 acted via COX-2 to stimulate cell proliferation and tissue regeneration. This indicates that low levels of active Caspase-3 may represent a new predictor of CT responsiveness, and inhibition of Caspase-3, or antagonising downstream effectors of Caspase-3 paracrine signalling, such as COX-2 may improve patient outcomes following CT in advanced CRC.
Highlights
Most common chemotherapeutics lead to the induction of apoptosis in the targeted cancer cell
To explore the association of Caspase-3 with patient outcome, we examined tissue microarrays (TMAs) consisting of tumour tissue from a total of 93 Colorectal cancer (CRC) patients
Following the recommendations made in the American Society of Clinical Oncology (ASCO)–College of American Pathologists (CAP) Test Guideline,[15] a cutoff value of 1% of stained cells was used to discriminate between positive (41%) and negative (o1%) cases.[16]
Summary
Most common chemotherapeutics lead to the induction of apoptosis in the targeted cancer cell. Patients with poor prognosis display highly proliferating tumours.[8,9] It has been demonstrated in a model of head regeneration in hydra that caspases are required for nuclear translocation of β-catenin and Wnt signalling during regeneration, linking for the first time caspase activation mechanistically with tissue regeneration.[10] Cyclooxygenase-2 (COX-2) activation may link these two processes: It is known that Wnt activation in cancer tissue and cancer stem cells is activated by Prostaglandin E2 (PGE2), which is produced predominantly from arachidonic acid (AA) by COX and Prostaglandine E synthases.[11] Zhao et al.[12] showed that Caspase-3 generates a truncated, active form of calcium-independent Phospholipase A2, iPLA2 (514–806). We examined Caspase-3 as a prognostic marker in stage 2/3 as well as in metastatic CRC patients, and further explored the role of caspase-3 as a potential predictive biomarker for 5FU-based CT and therapeutic target in CRC using primary human tumour explant culture
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