Major Finding: Timp1 status in Pten-null prostate cancer cells dictated whether senescence was detrimental in vivo.
Concept: Loss of Timp1 increased metastasis in mice, and low-TIMP1 patient tumors portended poor prognosis.
Impact: This work clarifies why studies on the impact of cellular senescence on cancer have been conflicting.
The role of cellular senescence in cancer is complex, with some studies demonstrating a link between senescence and unfavorable disease characteristics and others showing the opposite. To investigate this, Guccini, Revandkar, and colleagues employed a mouse model of indolent prostate cancer that exhibits a tumor-suppressive p53-mediated senescence response due to conditional inactivation of Pten in the prostate. Using this model, it was revealed that loss of Timp1 (encoding a metalloproteinase inhibitor) increased primary tumor growth and metastasis. Notably, specific pharmacologic ablation of senescent cells using a BCL2 inhibitor in the Pten-null Timp1-null mouse prostate cancer model hindered metastasis. In the same model, therapy-induced senescence caused by docetaxel treatment caused metastasis to occur more rapidly than with vehicle control, but this was not the case when Timp1 was functional despite the fact that Timp1-competent tumors also exhibited increased expression of senescence-linked genes. Corroborating the results observed in the transgenic mouse models, mice injected with TIMP1-knockdown human PTEN-null prostate cancer cells had increased tumor cell colonization of the lungs and kidneys following treatment with docetaxel, and these colonizing tumor cells expressed senescence markers at high levels. In comparison, TIMP1-competent lung- and kidney-colonizing human prostate cancer cells formed smaller tumors after docetaxel treatment. Further, pharmacologic inhibition of BCL2 to target senescent cells prevented docetaxel treatment–mediated lung and kidney colonization by TIMP1-deficient prostate cancer cells. Mechanistically, Timp1 deficiency altered the senescence-associated secretory phenotype of Pten-null cancer cells (as a result of loss of TIMP1-mediated metalloproteinase inhibitor activity affecting secreted factors) in a manner such that cell migration was promoted. Highlighting the potential clinical relevance of these findings, a prospective analysis of adjuvant docetaxel treatment following surgery patients with high-risk localized prostate cancer revealed that low tumor TIMP1 expression was correlated with poor prognosis, and loss of both TIMP1 and PTEN portended the worst outcomes of all. In summary, this study identifies a key factor mediating the impact of senescence on outcomes in prostate cancer.
Notes
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
- ©2021 American Association for Cancer Research.
Volume 11, Issue 1
