Elevated cleaved caspase-3 is associated with shortened overall survival in several cancer types.
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Emerging evidence has indicated that apoptotic cells have a compensatory effect on the proliferation of neighboring cells. Recent studies have shown that apoptotic tumor cells stimulate the repopulation of tumors from a small number of surviving cells by cleaved caspase-3 regulation and elevated tumor cleaved (and thus activated) caspase-3 expression levels predict worse treatment outcomes in cancer patients. The prognostic significance of cleaved caspase-3 should be demonstrated in more human cancer types and larger subjects. Here, we examined the cleaved caspase-3 expression in 367 human tumor samples (gastric cancer: 97 cases, ovarian cancer: 65 cases, cervical cancer: 104 cases; colorectal cancer: 101 cases) with immunohistochemistry (IHC) and the relationship between the expression of cleaved caspase-3 and various clinicopathological factors were also detected. We found that, cleaved caspase-3 was significantly associated with pathological risk factors (P < 0.005) for the studied cancers, such as tumor stage, lymph-node metastasis, differentiation and so on. In univariate and multivariate analysis, patients with high expression of cleaved caspase-3 had a significant shorter overall survival time compared with those with low cleaved caspase-3 expression in gastric cancer (P < 0.001), ovarian cancer (P < 0.001), cervical cancer (P = 0.002), colorectal cancer (P < 0.001) individually and in the patients combined (P < 0.001). Cox regression results suggested cleaved caspase-3 as an independent prognosis predictor for the studied four cancer types. Our study showed cleaved caspase-3 was well correlated to progression, aggressive behaviors in the studied cancer, and implicated it as a potential predictive factor for the prognosis of the four cancer types. It also indicated cleaved caspase-3 as a potential therapeutic target for cancer patients.Cite
Emerging evidence has indicated that apoptotic cells have a compensatory effect on the proliferation of neighboring cells. However, the potential role of dying vascular endothelial cells (ECs) in glioma tumor proliferation remains unclear. In the present study, three glioma cell lines were cocultured with dying ECs under various conditions to evaluate the effect of dying ECs on tumor proliferation using alamarBlue and trypan blue assays to assess cell proliferation and viability, respectively. The results suggested that dying ECs had a marked ability to facilitate glioma cell growth via a caspase 3‑mediated pathway. Furthermore, calcium‑independent phospholipase A2 (iPLA2), a downstream gene regulated by caspase 3, is highly involved in this process. Prostaglandin E2 (PGE2) was the final effector of the caspase 3‑iPLA2 signaling pathway in glioma cell proliferation. Knockdown of caspase 3 or iPLA2 using shRNA negated the growth stimulating effect of dying ECs. By contrast, the overexpression of iPLA2 in ECs via the pLEX lentiviral vector system or addition of PGE2 into culture medium had a growth promoting effect on glioma cells. Overall, the present data revealed a paracrine signal released from dying ECs which promotes the proliferation of surrounding glioma cells, demonstrating the importance of blocking compensatory proliferation during tumor therapy. Additionally, targeting caspase 3‑mediated pathways combined with current therapeutic strategies may be a promising approach for improving the dismal prognosis associated with these malignant tumors.
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BackgroundCells undergoing apoptosis are known to modulate their tissue microenvironments. By acting on phagocytes, notably macrophages, apoptotic cells inhibit immunological and inflammatory responses and promote trophic signaling pathways. Paradoxically, because of their potential to cause death of tumor cells and thereby militate against malignant disease progression, both apoptosis and tumor-associated macrophages (TAMs) are often associated with poor prognosis in cancer. We hypothesized that, in progression of malignant disease, constitutive loss of a fraction of the tumor cell population through apoptosis could yield tumor-promoting effects.ResultsHere, we demonstrate that apoptotic tumor cells promote coordinated tumor growth, angiogenesis, and accumulation of TAMs in aggressive B cell lymphomas. Through unbiased "in situ transcriptomics" analysis—gene expression profiling of laser-captured TAMs to establish their activation signature in situ—we show that these cells are activated to signal via multiple tumor-promoting reparatory, trophic, angiogenic, tissue remodeling, and anti-inflammatory pathways. Our results also suggest that apoptotic lymphoma cells help drive this signature. Furthermore, we demonstrate that, upon induction of apoptosis, lymphoma cells not only activate expression of the tumor-promoting matrix metalloproteinases MMP2 and MMP12 in macrophages but also express and process these MMPs directly. Finally, using a model of malignant melanoma, we show that the oncogenic potential of apoptotic tumor cells extends beyond lymphoma.ConclusionsIn addition to its profound tumor-suppressive role, apoptosis can potentiate cancer progression. These results have important implications for understanding the fundamental biology of cell death, its roles in malignant disease, and the broader consequences of apoptosis-inducing anti-cancer therapy.
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SOLID tumors are composed of two discrete but interdependent compartments: the malignant cells themselves and the stroma that they induce and in which they are dispersed.1 , 2 In tumors of epithelialcell origin — carcinomas — a basement membrane is often interposed between the tumor cells and the stroma, but in other types of tumors, malignant cells directly abut on or intermingle with stromal elements.1 , 3 An appreciation of tumor stroma is essential to an understanding of the biology of tumor growth; all solid tumors, regardless of their site of origin, require stroma if they are to grow beyond a minimal size of . . .
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David R. McIlwain1,2, Thorsten Berger1 and Tak W. Mak The Campbell Family Institute for Breast Cancer Research and Ontario Cancer Institute, University Health Network, Toronto, Ontario M5G 2C1, Canada Correspondence: tmak{at}uhnres.utoronto.ca ↵1 These authors contributed equally to this work. ↵2 Present address: Department of Gastroenterology, Hepatology and Infectious Diseases, University of Düsseldorf, 40225 Düsseldorf, Germany.
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