Blocking IL1β Pathway Following Paclitaxel Chemotherapy Slightly Inhibits Primary Tumor Growth but Promotes Spontaneous Metastasis

Voloshin, Tali; Alishekevitz, Dror; Kaneti, Limor; Miller, Valeria; Isakov, Elina; Kaplanov, Irena; Voronov, Elena; Fremder, Ella; Benhar, Moran; Machluf, Marcelle; Apte, Ron N.; Shaked, Yuval

doi:10.1158/1535-7163.mct-14-0969

Cited by 65 publications

(57 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Both mouse and human Endothelin 1 mRNA levels was decreased 2 fold and 2.8 fold respectively following administration of anakinra via the treatment or preventative protocols compared with placebo (P < 0.01; Figure 2e). Repeated administration of a higher dose of anakinra, 10mg/kg, have previously been shown to increase macrophage infiltration into tumours [24]. In our current study 1mg/kg/day anakinra did not affect macrophage infiltration into tumours within bone (Figure 2f).…”

Section: Resultssupporting

confidence: 53%

“…Our data suggest that these anti-tumour effects are a result of changes in the tumour microenvironment, as direct incubation of MDA-MB-231-IV cells with anakinra did not exert anti-tumour affects in vitro (Supplementary Figure S1). The bone is rich in remodelling cytokines, including TNF alpha, IL-1B and IL-6, and previous studies have reported that incubation of MDA-MB-231 cells with a combination of these cytokines in a 3D model system stimulates their proliferation [24]. In our study, administration of anakinra significantly reduced expression of TNF alpha and IL-1B in bone (Figure 3) and reduced levels of these molecules is likely to have contributed to the anti-tumour effects observed.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

IL-1 drives breast cancer growth and bone metastasisin vivo

et al. 2016

View full text Add to dashboard Cite

BackgroundWe have recently identified interleukin 1B (IL-1B) as a potential biomarker for predicting breast cancer patients at increased risk for developing bone metastasis. In mouse models, IL-1B and its receptor (IL-1R1) are upregulated in breast cancer cells that metastasise to bone compared with cells that do not. We have now investigated the functional role of IL-1 by blocking IL-1R signalling with the clinically licensed antagonist, anakinra.Methodology6-week old female BALB/c mice received a subcutaneous or intra-venous injection of MDA-MB-231-IV or MCF7 cells. Anakinra (1mg/kg/day) or placebo was administered 3 days before (preventative) or 7 days later (treatment). Tumour volume, apoptosis (TUNEL, Caspase 3), proliferation (Ki67) and angiogenesis (CD34, VEGF and endothelin) were analysed. Effects on bone were measured by uCT, and TRAP, P1NP, IL-1B, TNF alpha and IL-6 ELISA.ResultsAnakinra significantly reduced growth of MDA-MB-231-IV tumours in bone from 6.50+/3.00mm2 (placebo) to 2.56+/−1.07mm2 (treatment) and 0.63+/−0.18mm2 (preventative). Anakinra also reduced the number of mice that developed bone metastasis from 90% (placebo) to 40% (treatment) and 10% (preventative). Anti-tumour effects were not confined to bone, subcutaneous tumour volumes reduced from 656.68mm3 (placebo) to 160.47mm3 (treatment) and 31.08mm3 (preventative). Anakinra did not increase tumour cell apoptosis but reduced proliferation and angiogenesis in addition to exerting significant effects on the tumour environment reducing bone turnover markers, IL-1B and TNF alpha.ConclusionsOur novel data demonstrate a functional role of IL-1 signalling in breast tumour progression and metastasis, supporting that anakinra could be repurposed for the treatment of breast cancer bone metastasis.

show abstract

Section: Resultssupporting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

IL-1 drives breast cancer growth and bone metastasisin vivo

et al. 2016

View full text Add to dashboard Cite

show abstract

“…We have previously shown that following PTX therapy, the balance between M1 and M2 macrophages is disrupted in tumors. The blockade of interleukin 1β (IL-1β) in PTX-treated mice results in an increased number of infiltrating M2 macrophages in tumors, leading to increased metastasis (Voloshin et al., 2015). Thus, the specific macrophage state that contributes to tumor lymphangiogenesis following PTX therapy remains to be established.…”

Section: Discussionmentioning

confidence: 99%

“…Bone marrow transplantation was performed as previously described (Voloshin et al., 2015). Details are provided in Supplemental Experimental Procedures.…”

Section: Methodsmentioning

confidence: 99%

Macrophage-Induced Lymphangiogenesis and Metastasis following Paclitaxel Chemotherapy Is Regulated by VEGFR3

et al. 2016

Self Cite

View full text Add to dashboard Cite

SummaryWhile chemotherapy strongly restricts or reverses tumor growth, the response of host tissue to therapy can counteract its anti-tumor activity by promoting tumor re-growth and/or metastases, thus limiting therapeutic efficacy. Here, we show that vascular endothelial growth factor receptor 3 (VEGFR3)-expressing macrophages infiltrating chemotherapy-treated tumors play a significant role in metastasis. They do so in part by inducing lymphangiogenesis as a result of cathepsin release, leading to VEGF-C upregulation by heparanase. We found that macrophages from chemotherapy-treated mice are sufficient to trigger lymphatic vessel activity and structure in naive tumors in a VEGFR3-dependent manner. Blocking VEGF-C/VEGFR3 axis inhibits the activity of chemotherapy-educated macrophages, leading to reduced lymphangiogenesis in treated tumors. Overall, our results suggest that disrupting the VEGF-C/VEGFR3 axis not only directly inhibits lymphangiogenesis but also blocks the pro-metastatic activity of macrophages in chemotherapy-treated mice.

show abstract

“…Thus, dual effects of blocking the IL1 pathway on tumor growth are possible. Therefore, treatments using “add-on” drugs such as the IL-1β blocker to conventional chemotherapy should be investigated in appropriate tumor models monitoring both the primary tumor and the induction of metastases [278]. …”

Section: Anti-cancer Agents Induce Il-1βmentioning

confidence: 99%

Interleukin-1 Beta—A Friend or Foe in Malignancies?

Bent

Moll

Grabbe

et al. 2018

IJMS

319

221

View full text Add to dashboard Cite

Interleukin-1 beta (IL-1β) is induced by inflammatory signals in a broad number of immune cell types. IL-1β (and IL-18) are the only cytokines which are processed by caspase-1 after inflammasome-mediated activation. This review aims to summarize current knowledge about parameters of regulation of IL-1β expression and its multi-facetted role in pathophysiological conditions. IL-1 signaling activates innate immune cells including antigen presenting cells, and drives polarization of CD4+ T cells towards T helper type (Th) 1 and Th17 cells. Therefore, IL-1β has been attributed a largely beneficial role in resolving acute inflammations, and by initiating adaptive anti-tumor responses. However, IL-1β generated in the course of chronic inflammation supports tumor development. Furthermore, IL-1β generated within the tumor microenvironment predominantly by tumor-infiltrating macrophages promotes tumor growth and metastasis via different mechanisms. These include the expression of IL-1 targets which promote neoangiogenesis and of soluble mediators in cancer-associated fibroblasts that evoke antiapoptotic signaling in tumor cells. Moreover, IL-1 promotes the propagation of myeloid-derived suppressor cells. Using genetic mouse models as well as agents for pharmacological inhibition of IL-1 signaling therapeutically applied for treatment of IL-1 associated autoimmune diseases indicate that IL-1β is a driver of tumor induction and development.

show abstract

Blocking IL1β Pathway Following Paclitaxel Chemotherapy Slightly Inhibits Primary Tumor Growth but Promotes Spontaneous Metastasis

Cited by 65 publications

References 31 publications

IL-1 drives breast cancer growth and bone metastasisin vivo

IL-1 drives breast cancer growth and bone metastasisin vivo

Macrophage-Induced Lymphangiogenesis and Metastasis following Paclitaxel Chemotherapy Is Regulated by VEGFR3

Interleukin-1 Beta—A Friend or Foe in Malignancies?

Contact Info

Product

Resources

About