Senescence Reprogramming by TIMP1 Deficiency Promotes Prostate Cancer Metastasis

Guccini, Ilaria; Revandkar, Ajinkya; D’Ambrosio, Mariantonietta; Colucci, Manuel; Pasquini, Emiliano; Mosole, Simone; Troiani, Martina; Brina, Daniela; Sheibani-Tezerji, Raheleh; Elia, Angela Rita; Rinaldi, Andrea; Pernigoni, Nicolò; Rüschoff, Jan H.; Dettwiler, Susanne; Marzo, Angelo M. De; Antonarakis, Emmanuel S.; Borrelli, Costanza; Moor, Andreas E.; García-Escudero, Ramón; Alajati, Abdullah; Attanasio, Giuseppe; Losa, Marco; Moch, Holger; Wild, Peter J.; Egger, Gerda; Alimonti, Andrea

doi:10.1016/j.ccell.2020.10.012

Cited by 96 publications

(94 citation statements)

References 59 publications

(79 reference statements)

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“…Loss of PTEN is observed in as many as 40% of PCa cases [ 258 ], and this mutation promotes PCa progression by activating CXCL8 [ 260 ] or NF-κB signaling and increasing the infiltration of MDSCs, Treg, and M2 macrophages [ 261 ]. Interestingly, PTEN -null tumor cells exhibit a prominent senescent phenotype [ 262 ], and are characterized by the excessive production of several tumor-promoting inflammatory cytokines, the so-called SASP, and the establishment of an immunosuppressive TME by themselves [ 263 ].…”

Section: Role Of Inflammation In Cancer Typesmentioning

confidence: 99%

Inflammation-Induced Tumorigenesis and Metastasis

Hibino

Kawazoe

Kasahara

et al. 2021

IJMS

142

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Inflammation, especially chronic inflammation, plays a pivotal role in tumorigenesis and metastasis through various mechanisms and is now recognized as a hallmark of cancer and an attractive therapeutic target in cancer. In this review, we discuss recent advances in molecular mechanisms of how inflammation promotes tumorigenesis and metastasis and suppresses anti-tumor immunity in various types of solid tumors, including esophageal, gastric, colorectal, liver, and pancreatic cancer as well as hematopoietic malignancies.

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Section: Role Of Inflammation In Cancer Typesmentioning

confidence: 99%

Inflammation-Induced Tumorigenesis and Metastasis

Hibino

Kawazoe

Kasahara

et al. 2021

IJMS

142

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“…Intravenously (I.V.) injection was performed in this study as previously reported [ 19 ]. Briefly, each group of PCa cells (5 × 10 5 ) were resuspended in 100 µL PBS and slowly injected into the tail vain of the mice.…”

Section: Methodsmentioning

confidence: 99%

Identification of novel key genes associated with the metastasis of prostate cancer based on bioinformatics prediction and validation

et al. 2021

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Background Metastatic prostate cancer (PCa) is a lethal tumor. However, the molecular mechanisms underlying PCa progression have not been fully elucidated. Methods Transcriptome expression profiling and clinical information on primary and metastatic PCa samples were obtained from TCGA. R software was used to screen the DEGs, and LASSO logistical regression method was utilized to identify the pivotal PCa metastasis-related DEGs. The transcriptional expression levels of the key genes were analyzed using the UALCAN database, and the corresponding protein expression were validated by Immunohistochemistry (IHC). Survival analysis of the key genes was performed using the GEPIA database. Wound healing assay and Transwell assay were conducted to determine whether knockdown of the key genes influence the migration and invasion abilities of PCa cells (22Rv1 and PC3). GSEA was performed to predict key genes-mediated signaling pathways for the development of PCa. Western blotting was used to evaluate the expression changes of E-cadherin, Twist1, and Vimentin in PCa cells with the key genes silencing. An in vivo mouse metastatic model for PCa was also generated to verify the important role of ISG15 and CST2 in PCa metastasis. Results A comparison between primary and metastatic PCa tissues was conducted, and 19 DEGs were screened. Among these, three key genes were identified that might be closely associated with PCa progression according to the LASSO logistical analysis, namely ISG15, DNAH8, and CST2. Further functional experiments revealed that knockdown of ISG15 and CST2 suppressed wound healing, migration, and invasion of PCa cells. To explore the molecular mechanism of ISG15 and CST2 in the development of PCa, GSEA was performed, and it was found that both genes play crucial roles in cell adhesion molecules, extracellular matrix-receptor interaction, and focal adhesion. Western blotting results exhibited that inhibiting ISG15 and CST2 led to increase the expression of E-cadherin and decrease the expression of Twist1 and Vimentin. Additionally, the metastatic in vivo study demonstrated that both PC3 and 22Rv1 cells expressing with luciferase-shISG15 and luciferase-shCST2 had significantly lower detectable bioluminescence than that in the control PCa cells. Conclusion ISG15 and CST2 may participate in PCa metastasis by regulating the epithelial-mesenchymal transition (EMT) signaling pathway. These findings may help to better understand the pathogenetic mechanisms governing PCa and provide promising therapeutic targets for metastatic PCa therapy.

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“…For example, GX15-070 (obatoclax mesylate), a BCL-2 inhibitor, was shown to improve bromodomain and extra-terminal protein inhibitors (BETi) in TNBC [84]. Similarly, another BCL-2 inhibitor, ABT-263 (Navitoclax), was reported to eliminate senescent cells and enhance the efficacy of olaparib, a poly(ADP ribose) polymerase (PARP) inhibitor, in both breast and ovarian cancer cell lines [85]. Furthermore, in a pre-clinical model of prostate cancer, TIMP1 loss, a panmatrix metalloproteinase inhibitor, was reported to promote metastasis in senescent tumours [86].…”

Section: Senolytics and Senostatics: Targeting And Utilising The Saspmentioning

confidence: 99%

“…When targeting TIMP1-deficient senescent tumour cells with ABT-263, the authors showed that the metastatic potential was significantly reduced. Moreover, docetaxel treatment, which is standard chemotherapy for prostate cancer, perpetrated TIS and exacerbated metastasis in TIMP1-deficient cancer cells, but this reaction could be rescued with ABT-263, thereby reducing metastatic events [86]. Balakrishnan et al (2020) have recently used obatoclax, a BH3 mimetic, in diffuse intrinsic pontine glioma (DIPG), an aggressive paediatric brain tumour.…”

Section: Senolytics and Senostatics: Targeting And Utilising The Saspmentioning

confidence: 99%

Overcoming the senescence‐associated secretory phenotype (SASP): a complex mechanism of resistance in the treatment of cancer

et al. 2021

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Senescence is a cellular state in which cells undergo persistent cell cycle arrest in response to non-lethal stress. In the treatment of cancer, senescence induction is a potent method of suppressing tumour cell proliferation. In spite of this, senescent cancer cells and adjacent non-transformed cells of the tumour microenvironment can remain metabolically active, resulting in paradoxical secretion of pro-inflammatory factors, collectively termed the senescenceassociated secretory phenotype (SASP). The SASP plays a critical role in tumourigenesis, affecting numerous processes including invasion, metastasis, epithelial-to-mesenchymal transition (EMT) induction, therapy resistance and immunosuppression, among others. With increasing evidence, it is becoming clear that cell type, tissue of origin and the primary cellular stressor are key determinants in how the SASP will influence tumour development and progression, including whether it will be pro-or anti-tumourigenic. In this review, we will focus on recent evidence regarding therapy-induced senescence (TIS) from anti-cancer agents, including chemotherapy, radiation, immunotherapy, and targeted therapies, and how each therapy can trigger the SASP, which in turn influences treatment efficacy. We will also discuss novel pharmacological manipulation of senescent cancer cells and the SASP, which offers an exciting and contemporary approach to cancer therapeutics. With future research, these adjuvant options may help to mitigate many of the negative side effects and pro-tumorigenic roles that are currently associated with TIS in cancer.

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Senescence Reprogramming by TIMP1 Deficiency Promotes Prostate Cancer Metastasis

Cited by 96 publications

References 59 publications

Inflammation-Induced Tumorigenesis and Metastasis

Inflammation-Induced Tumorigenesis and Metastasis

Identification of novel key genes associated with the metastasis of prostate cancer based on bioinformatics prediction and validation

Overcoming the senescence‐associated secretory phenotype (SASP): a complex mechanism of resistance in the treatment of cancer

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