**9. Conclusions**

Breast cancer is a heterogeneous disease and thus, highly variable across individual patients. This heterogenicity arises not only due to the diversity of genetic and molecular aberrations in primary breast cancer cells but also due to the diversity of cellular populations that inhabit the breast tumor microenvironment. Although IL-6 levels are higher in breast tumors and patient sera, the precise source of this IL-6 remains elusive. Importantly, many breast tumor stromal cells provide a paracrine source of IL-6 for breast cancer cells within the breast tumor microenvironment. In addition, certain clinical subtypes of breast cancers and research models, such as ERα-negative primary breast cancers and ERα-negative breast cancer cell lines, produce excessive IL-6 (Figure 2). Therefore, ERα-negative breast cancer cells may supply the tumor microenvironment with IL-6 by means of autocrine IL-6 production to exacerbate the poor prognosis associated with this clinical subtype. It will be critical to determine the specific cellular source of breast tumor-associated IL-6 to advance our understanding of this pleiotropic cytokine in breast cancer progression and metastasis. Moreover, this knowledge will facilitate the validation and subsequent clinical utility of current and novel targeted antagonists of the IL-6/STAT3 signaling network in breast cancer.

Fig. 2. Breast cancer cell ERα status dictates paracrine vs. autocrine IL-6 utilization.

### **10. References**

174 Breast Cancer – Focusing Tumor Microenvironment, Stem Cells and Metastasis

mechanisms underlying IL-6/STAT3 signaling in breast cancer cells such as enhanced growth, induction of EMT, multidrug resistance, and recruitment of peripheral fibroblasts. Taken together, accumulating preclinical and clinical data emphasize IL-6 as a highly attractive therapeutic target in breast cancer. It is therefore imperative that more work be done to evaluate current therapeutics and develop novel agents that target IL-6/STAT3

Multiple strategies could be utilized to target the IL-6/STAT3 pathway, but first and most obvious would be anti-IL-6 neutralizing antibodies. One such anti-IL-6 monoclonal antibody is Siltuximab (CNTO 328). The safety and efficacy of Situximab has been demonstrated in preclinical studies and phase I/II clinical trials of diverse human pathologies and malignancies including Castleman's disease (van Rhee *et al.*, 2010), multiple myeloma (Hunsucker *et al.*, 2011; Voorhees *et al.*, 2007), prostate cancer (Cavarretta *et al.*, 2007; Cavarretta *et al.*, 2008; Dorff *et al.*, 2010; Karkera *et al.*, 2011), renal cell carcinoma (Puchalski *et al.*, 2010; Rossi *et al.*, 2010), non-small cell lung cancer (Song *et al.*, 2010), and ovarian cancer (Guo *et al.*, 2010). Furthermore, IL-6R can be targeted with tocilizumab, an anti-IL-6R monoclonal antibody that has shown promising results in IL-6 driven autoimmune diseases (Tanaka et al., 2011) and was recently approved by the FDA for the treatment of rheumatoid arthritis. The promiscuous IL-6 coreceptor, gp130, also has an endogenous soluble form (sgp130) that exclusively inhibits IL-6 *trans*-signaling, thus preserving classical IL-6 signaling. Therapeutic sgp130 would potentially be more targeted toward breast cancer cells, which generally lack membrane-associated IL-6R and therefore utilize IL-6 trans-signaling through IL-6sR. Recombinant soluble gp130 (sgp130- Fc) has been shown to inhibit murine colon carcinogenesis (Becker *et al.*, 2004), suggesting that it may prove effective in breast cancer as well. Finally, a growing number of nonselective kinase inhibitors and recent focus on specific JAK and STAT3 inhibitor development will provide further insight into the roles of JAK and STAT3 in breast

Breast cancer is a heterogeneous disease and thus, highly variable across individual patients. This heterogenicity arises not only due to the diversity of genetic and molecular aberrations in primary breast cancer cells but also due to the diversity of cellular populations that inhabit the breast tumor microenvironment. Although IL-6 levels are higher in breast tumors and patient sera, the precise source of this IL-6 remains elusive. Importantly, many breast tumor stromal cells provide a paracrine source of IL-6 for breast cancer cells within the breast tumor microenvironment. In addition, certain clinical subtypes of breast cancers and research models, such as ERα-negative primary breast cancers and ERα-negative breast cancer cell lines, produce excessive IL-6 (Figure 2). Therefore, ERα-negative breast cancer cells may supply the tumor microenvironment with IL-6 by means of autocrine IL-6 production to exacerbate the poor prognosis associated with this clinical subtype. It will be critical to determine the specific cellular source of breast tumor-associated IL-6 to advance our understanding of this pleiotropic cytokine in breast cancer progression and metastasis. Moreover, this knowledge will facilitate the validation and subsequent clinical utility of current and novel targeted antagonists of the IL-6/STAT3 signaling network in breast

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**9** 

*USA* 

**The Role of Fibrin(ogen) in Transendothelial** 

Patricia J. Simpson-Haidaris1, Brian J. Rybarczyk2 and Abha Sahni3 *1Department of Medicine, University of Rochester School of Medicine and Dentistry,* 

> *2Department of Biology, University of North Carolina at Chapel Hill, 3Aab Cardiovascular Research Institute, University of Rochester*

> > *School of Medicine and Dentistry,*

**Cell Migration During Breast Cancer Metastasis** 

Despite all the modern advances in treatment for breast cancer, metastatic disease remains the hurdle to surmount in curing breast cancer or, at least, in significantly reducing morbidity and mortality to improve long-term survival and quality of life. For over a century, inflammation and thrombosis have been linked to metastatic cancer (Boccaccio & Medico, 2006). In addition to being known for describing the factors leading to venous thromboembolism (alterations in blood flow, vascular endothelial injury, and hypercoagulability) as Virchow's triad, in 1863 Virchow noted a connection between chronic inflammation and cancer based on the recruitment of leukocytes to cancerous lesions

Fig. 1. The three faces of cancer metastasis. (Portraits obtained from public domain).

**1. Introduction** 

(reviewed in (Balkwill & Mantovani, 2001)) (**Fig. 1**).

