We have investigated the importance of interleukin-6 (IL-6) in promoting tumor growth and metastasis. In human primary breast cancers, increased levels of IL-6 were found at the tumor leading edge ...and positively correlated with advanced stage, suggesting a mechanistic link between tumor cell production of IL-6 and invasion. In support of this hypothesis, we showed that the IL-6/Janus kinase (JAK)/signal transducer and activator of transcription 3 (Stat3) pathway drives tumor progression through the stroma and metastatic niche. Overexpression of IL-6 in tumor cell lines promoted myeloid cell recruitment, angiogenesis, and induced metastases. We demonstrated the therapeutic potential of interrupting this pathway with IL-6 receptor blockade or by inhibiting its downstream effectors JAK1/2 or Stat3. These clinically relevant interventions did not inhibit tumor cell proliferation
in vitro
but had profound effects
in vivo
on tumor progression, interfering broadly with tumor-supportive stromal functions, including angiogenesis, fibroblast infiltration, and myeloid suppressor cell recruitment in both the tumor and pre-metastatic niche. This study provides the first evidence for IL-6 expression at the leading edge of invasive human breast tumors and demonstrates mechanistically that IL-6/JAK/Stat3 signaling plays a critical and pharmacologically targetable role in orchestrating the composition of the tumor microenvironment that promotes growth, invasion, and metastasis.
Abstract
Non-small cell lung cancer (NSCLC) is the leading cause of death in the United States. A fraction of these tumors harbor somatic activating mutations in the epidermal growth factor receptor ...(EGFR) leading to constitutive activation of the kinase. Targeting this pathway using a class of tyrosine kinase inhibitors (TKI) such as gefitinib or erlotinib induces significant initial responses in patients with NSCLC expressing activating EGFR mutations, however, disease progression invariably occurs in part due to the outgrowth of cancers with EGFR TKI resistant secondary mutations. There are many ongoing attempts to overcome this problem, but the current efforts are mostly focused on EGFR itself and their effectiveness remains inconclusive. The interleukin-6 (IL-6) /Jak/Stat3 signaling pathway is critical not only for inflammation and immunity, but also for oncogenesis. Stat3 is persistently activated in many human cancers, promoting tumorigenesis through the regulation of genes important for proliferation, apoptosis, invasion, angiogenesis and suppression of anti-tumor immunity. We previously determined that Stat3 is activated in mutant EGFR expressing NSCLC cell lines and primary tumors in part through autocrine upregulation of the IL-6 gene that activates the gp130/Jak signaling. In our current report, we studied the in vivo effect of inhibiting the IL-6/Jak/Stat3 signaling in EGFR TKI-resistant models of NSCLC. Our data demonstrated that Jak inhibition by a novel orally available Jak inhibitor markedly repressed in vivo growth of 3 different TKI resistant NSCLC cell lines as well as a TKI sensitive cell line. Immunohistochemical analyses of these samples revealed reduced proliferation and angiogenesis in Jak inhibitor treated tumors. In addition, administration of an IL-6R blocking antibody to xenograft tumors of a TKI resistant NSCLC cell line also achieved significant reduction in tumor growth compared to controls. We further tested the potential role of IL-6 in a transgenic murine model of TKI-resistant, mutant EGFR mediated lung cancer. Our results demonstrated mice lacking IL-6 still developed lung tumors but at a much slower rate of tumor progression compared to IL-6 expressing littermates. Additional examinations showed that mice lacking IL-6 developed tumors with papillary features compared to IL-6 expressing littermates whereas most of the tumors were of the more advanced, solid/pleiomorphic subtype. IL-6 deficient lung tumors had decreased proliferation and angiogenesis compared to tumors from wildtype littlermates. In summary, our findings lead us to hypothesize that the IL-6/Jak pathway should be considered as a novel therapeutic target for this disease, especially TKI resistant NSCLC.
Citation Format: {Authors}. {Abstract title} abstract. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4689. doi:10.1158/1538-7445.AM2011-4689
Stat3 is for the development of skin cancer Pedranzini, Laura; Leitch, Andrea; Bromberg, Jacqueline
The Journal of clinical investigation,
09/2004, Letnik:
114, Številka:
5
Journal Article
Recenzirano
Signal transducer and activator of transcription 3 (Stat3) is a transcription factor that is constitutively activated in a variety of human malignancies, including prostate, lung, brain, breast, and ...squamous cell carcinomas. Inhibition of activated Stat3 leads to decreased proliferation and apoptosis of many cancer-derived cell lines, while the introduction of a constitutively activated form of Stat3 into immortalized human breast epithelial cells and rodent fibroblasts results in cellular transformation. Collectively, these data suggest a role for Stat3 in oncogenesis. A new study from Chan et al. is the first to demonstrate a requirement for Stat3 in de novo epithelial carcinogenesis in vivo. Using the two-step model of chemically induced skin carcinogenesis, the authors demonstrated that mice deficient in Stat3 were completely resistant to skin tumor development.
Cancer stem cells Rajasekhar, Vinagolu K
2014., 2014, 20140101, 2014-01-27, 2014-01-23
eBook
Cancer Stem Cells covers a wide range of topics in cancer stem cell biology, including the functional characteristics of cancer stem cells and how they're generated, where they are localized, the ...means by which cancer stem cells can be targeted, and how cancer stem cells can be reprogrammed back to normal tissue stem cells. Each chapter begins with a brief historical note and concept summary, followed by a description of the latest basic or clinical advance associated with the topic. Cancer Stem Cells builds systematically from coverage of the basic research stage to an advanced research level, from clinical relevance to therapeutic potential, and will be a valuable resource for professionals in the fields of cancer research and stem cell biology.
The persistent activation of signal transducer and activator of transcription 3 (Stat3) is a common feature of prostate cancer. However, little is known about the Stat3 targets that may mediate ...prostate tumorigenesis. The introduction of an activating mutant form of Stat3 (Stat3-C) into immortalized prostate epithelial cells resulted in tumorigenesis. Stat3-C-expressing cells had decreased E-cadherin levels, increased numbers of lamellipodia and stress fibers, and enhanced migratory capacities compared to vector control-expressing cells, with a concomitant increase in the expression of integrin {szligbeta}6 and its ligand, fibronectin (FN). Exogenously added FN increased cellular migration, with a concomitant loss of E-cadherin expression. The blockade of integrin alpha v{szligbeta}6 in Stat3-C-expressing cells inhibited migration, increased E-cadherin levels, and reduced colony formation in soft agar. These results demonstrate the sufficiency of constitutively activated Stat3 in mediating prostate tumorigenesis and identify novel Stat3 targets that are involved in promoting cell migration and transformation.
The Wnt/beta-catenin/Tcf and IkappaB/NF-kappaB cascades are independent pathways involved in cell cycle control, cellular differentiation, and inflammation. Constitutive Wnt/beta-catenin signaling ...occurs in certain cancers from mutation of components of the pathway and from activating growth factor receptors, including RON and MET. The resulting accumulation of cytoplasmic and nuclear beta-catenin interacts with the Tcf/LEF transcription factors to induce target genes. The IkappaB kinase complex (IKK) that phosphorylates IkappaB contains IKKalpha, IKKbeta, and IKKgamma. Here we show that the cyclin D1 gene functions as a point of convergence between the Wnt/beta-catenin and IkappaB pathways in mitogenic signaling. Mitogenic induction of G(1)-S phase progression and cyclin D1 expression was PI3K dependent, and cyclin D1(-/-) cells showed reduced PI3K-dependent S-phase entry. PI3K-dependent induction of cyclin D1 was blocked by inhibitors of PI3K/Akt/IkappaB/IKKalpha or beta-catenin signaling. A single Tcf site in the cyclin D1 promoter was required for induction by PI3K or IKKalpha. In IKKalpha(-/-) cells, mitogen-induced DNA synthesis, and expression of Tcf-responsive genes was reduced. Reintroduction of IKKalpha restored normal mitogen induction of cyclin D1 through a Tcf site. In IKKalpha(-/-) cells, beta-catenin phosphorylation was decreased and purified IKKalpha was sufficient for phosphorylation of beta-catenin through its N-terminus in vitro. Because IKKalpha but not IKKbeta induced cyclin D1 expression through Tcf activity, these studies indicate that the relative levels of IKKalpha and IKKbeta may alter their substrate and signaling specificities to regulate mitogen-induced DNA synthesis through distinct mechanisms.
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