Cellular senescence in cancer treatment: friend or foe?

Kahlem, Pascal; Dörken, Bernd; Schmitt, Clemens A.

doi:10.1172/jci200420784

Cited by 57 publications

(47 citation statements)

References 51 publications

(31 reference statements)

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“…The major tumor-suppressor protein p53 is implicated in regulation of cell senescence both in primary and cancer cells (22,27). Therefore, we hypothesized that senescence triggered by depletion of Hsp72 in cancer cells may involve activation of p53 pathway.…”

Section: Resultsmentioning

confidence: 99%

High Levels of Heat Shock Protein Hsp72 in Cancer Cells Suppress Default Senescence Pathways

Yaglom

Gabai²,

Sherman³

2007

Cancer Research

103

106

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The major heat shock protein Hsp72 is constitutively expressed in many tumor cell lines and biopsies, and its expression correlates with poor prognosis in several types of cancer. Hsp72 was suggested to play an important role in neoplastic transformation and tumor development. We addressed the role of Hsp72 in cancer cells by investigating the consequences of specific depletion of Hsp72 using small interfering RNA. Downregulation of Hsp72 in certain cancer lines triggered cell senescence associated with activation and stabilization of p53 and induction of the cell cycle inhibitor p21. Effects of Hsp72 depletion on senescence and p53 did not result from a proteotoxic stress, DNA instability, or activation of ataxiatelangiectasia-mutated (ATM) and ATM-and Rad3-related pathways. Instead, depletion of Hsp72 reduced stability and activity of the p53 inhibitor Hdm2. In addition, Hsp72 depletion triggered a p53-independent senescence program through inhibitory phosphorylation and down-regulation of the cell cycle kinase Cdc2. Therefore, Hsp72 provides a selective advantage to cancer cells by suppressing default senescence via p53-dependent and p53-independent pathways.

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Section: Resultsmentioning

confidence: 99%

High Levels of Heat Shock Protein Hsp72 in Cancer Cells Suppress Default Senescence Pathways

Yaglom

Gabai²,

Sherman³

2007

Cancer Research

103

106

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“…Potential exists for development of therapeutic compounds that specifically induce senescence in cancer cells (Roninson, 2003). However, concerns have been raised regarding the promoting effect of senescent cancer cells on the tumour microenvironment, similar to that seen with senescent fibroblasts (Kahlem et al, 2004). Our results demonstrate that a limited proliferative response occurs in vitro with chemically induced senescent cells when compared to senescent fibroblasts (Figure 2A).…”

Section: Discussionmentioning

confidence: 99%

Drug-induced senescence bystander proliferation in prostate cancer cells in vitro and in vivo

et al. 2008

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Senescence is a distinct cellular response induced by DNA-damaging agents and other sublethal stressors and may provide novel benefits in cancer therapy. However, in an ageing model, senescent fibroblasts were found to stimulate the proliferation of cocultured cells. To address whether senescence induction in cancer cells using chemotherapy induces similar effects, we used GFP-labelled prostate cancer cell lines and monitored their proliferation in the presence of proliferating or doxorubicin-induced senescent cancer cells in vitro and in vivo. Here, we show that the presence of senescent cancer cells increased the proliferation of cocultured cells in vitro through paracrine signalling factors, but this proliferative effect was significantly less than that seen with senescent fibroblasts. In vivo, senescent cancer cells failed to increase the establishment, growth or proliferation of LNCaP and DU145 xenografts in nude mice. Senescent cells persisted as long as 5 weeks in tumours. Our results demonstrate that although drug-induced senescent cancer cells stimulate the proliferation of bystander cells in vitro, this does not significantly alter the growth of tumours in vivo. Coupled with clinical observations, these data suggest that the proliferative bystander effects of senescent cancer cells are negligible and support the further development of senescence induction as therapy.

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“…Although first described as the terminal state of cells with telomere dysfunction, recognized by the cell as a form of DNA damage, cellular senescence is now understood to be a general reaction of cells to a wide range of unrepairable DNA damage and may serve as a tumor suppressor mechanism (3)(4)(5). Senescent cells occur in tissues in vivo under various conditions (2).…”

Section: Introductionmentioning

confidence: 99%

“…Senescent cells occur in tissues in vivo under various conditions (2). Although senescent cells accumulate in aging, they are also present in a variety of pathologic conditions such as chronic ulcers, benign prostatic hypertrophy, and tissues damaged by radiation or chemotherapy (3,4,6).…”

Section: Introductionmentioning

confidence: 99%

Senescent Human Fibroblasts Increase the Early Growth of Xenograft Tumors via Matrix Metalloproteinase Secretion

Liú¹,

Hornsby²

2007

Cancer Research

401

328

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Although cellular senescence is believed to have a tumor suppressor function, senescent cells have been shown to increase the potential for growth of adjacent cancer cells in animal models. Replicatively senescent human fibroblasts increase the growth of cotransplanted cancer cells in vivo, but the role of cells that have undergone damage-mediated stressinduced premature senescence (SIPS) has not been studied in mouse transplant models. Here, we show that human fibroblasts that have undergone SIPS by exposure to the DNAdamaging agent bleomycin increase the growth of cotransplanted cancer cells (MDA-MB-231) in immunodeficient mice. Xenografts containing SIPS fibroblasts (SIPSF) exhibited early tissue damage as evidenced by fluid accumulation (edema). Cancer cells adjacent to the fluid showed increased DNA synthesis. Fluid accumulation, increased xenograft size, and increased cell proliferation were all reduced by the matrix metalloproteinase (MMP) inhibitor GM6001. MMPs and other genes characteristic of inflammation/tissue injury were overexpressed in SIPSF. Inhibition of MMP activity did not affect SIPSF stimulation of cancer cell proliferation in culture. However, another overexpressed product (hepatocyte growth factor) did have a direct mitogenic action on cancer cells.

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Cellular senescence in cancer treatment: friend or foe?

Cited by 57 publications

References 51 publications

High Levels of Heat Shock Protein Hsp72 in Cancer Cells Suppress Default Senescence Pathways

High Levels of Heat Shock Protein Hsp72 in Cancer Cells Suppress Default Senescence Pathways

Drug-induced senescence bystander proliferation in prostate cancer cells in vitro and in vivo

Senescent Human Fibroblasts Increase the Early Growth of Xenograft Tumors via Matrix Metalloproteinase Secretion

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