Prosenescence therapy has recently emerged as a novel therapeutic approach for treating cancer. However, this concept is challenged by conflicting evidence showing that the senescence-associated secretory phenotype (SASP) of senescent tumor cells can have pro- as well as antitumorigenic effects. Herein, we report that, in Pten-null senescent tumors, activation of the Jak2/Stat3 pathway establishes an immunosuppressive tumor microenvironment that contributes to tumor growth and chemoresistance. Activation of the Jak2/Stat3 pathway in Pten-null tumors is sustained by the downregulation of theprotein tyrosine phosphatase PTPN11/SHP2, providing evidence for the existence of a novel PTEN/SHP2 axis. Importantly, treatment with docetaxel in combination with a JAK2 inhibitor reprograms the SASP and improves the efficacy of docetaxel-induced senescence by triggering a strong antitumor immune response in Pten-null tumors. Altogether, these data demonstrate that immune surveillance of senescent tumor cells can be suppressed in specific genetic backgrounds but also evoked by pharmacological treatments.

Enhancing chemotherapy efficacy in pten-deficient prostate tumors by activating the senescence-associated antitumor immunity / A. Toso, A. Revandkar, D. Dimitri, I. Guccini, M. Proietti, M. Sarti, S. Pinton, J. Zhang, M. Kalathur, G. Civenni, D. Jarrossay, E. Montani, C. Marini, R. Garcia Escudero, E. Scanziani, F.M. Grassi, P. Pandolfi, C.V. Catapano, A. Alimonti. - In: CELL REPORTS. - ISSN 2211-1247. - 9:1(2014 Oct 09), pp. 75-89. [10.1016/j.celrep.2014.08.044]

Enhancing chemotherapy efficacy in pten-deficient prostate tumors by activating the senescence-associated antitumor immunity

M. Proietti;E. Scanziani;F.M. Grassi;
2014-10-09

Abstract

Prosenescence therapy has recently emerged as a novel therapeutic approach for treating cancer. However, this concept is challenged by conflicting evidence showing that the senescence-associated secretory phenotype (SASP) of senescent tumor cells can have pro- as well as antitumorigenic effects. Herein, we report that, in Pten-null senescent tumors, activation of the Jak2/Stat3 pathway establishes an immunosuppressive tumor microenvironment that contributes to tumor growth and chemoresistance. Activation of the Jak2/Stat3 pathway in Pten-null tumors is sustained by the downregulation of theprotein tyrosine phosphatase PTPN11/SHP2, providing evidence for the existence of a novel PTEN/SHP2 axis. Importantly, treatment with docetaxel in combination with a JAK2 inhibitor reprograms the SASP and improves the efficacy of docetaxel-induced senescence by triggering a strong antitumor immune response in Pten-null tumors. Altogether, these data demonstrate that immune surveillance of senescent tumor cells can be suppressed in specific genetic backgrounds but also evoked by pharmacological treatments.
Animals; Antineoplastic Agents; Cell Aging; Cytokines; Female; Gene Expression Profiling; Humans; Male; Mice; Mice, Transgenic; PTEN Phosphohydrolase; Prostatic Neoplasms; Signal Transduction; Taxoids; Tumor Microenvironment; Biochemistry, Genetics and Molecular Biology (all); Medicine (all)
Settore BIO/13 - Biologia Applicata
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/481322
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