Fibroblasts Isolated from Common Sites of Breast Cancer Metastasis Enhance Cancer Cell Growth Rates and Invasiveness in an Interleukin-6–Dependent Manner

Studebaker, Adam; Storci, Gianluca; Werbeck, Jillian L.; Sansone, Pasquale; Sasser, A. Kate; Tavolari, Simona; Huang, Tim Hui-Ming; Chan, Michael W.Y.; Marini, Frank C.; Rosol, Thomas J.; Bonafè, Massimiliano; Hall, Brett M.

doi:10.1158/0008-5472.can-08-0400

Cited by 207 publications

(205 citation statements)

References 50 publications

Supporting

Mentioning

190

Contrasting

Unclassified

Order By: Relevance

“…In addition, other groups showed that CM from CAFs has a growth-promoting effect on tumor cells due to factors secreted in the culture medium (14,15). Among these factors, IL-6, TGFbeta, COX-2, and CXCL14 have already been mentioned (16)(17)(18)(19)(20). Interestingly, we show that our results are in accordance with Erez et al in that the proinflammatory gene signature was up-regulated in our fibroblasts in vitro as well, except for SPP1, which showed down-regulation upon tumor cell confrontation (21).…”

Section: Discussionsupporting

confidence: 92%

Inhibition of tumor cell proliferation and motility by fibroblasts is both contact and soluble factor dependent

Alkasalias

Flaberg

Kashuba

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Normal human and murine fibroblasts can inhibit proliferation of tumor cells when cocultured in vitro. The inhibitory capacity varies depending on the donor and the site of origin of the fibroblast. We showed previously that effective inhibition requires formation of a morphologically intact fibroblast monolayer before seeding of the tumor cells. Here we show that inhibition is extended to motility of tumor cells and we dissect the factors responsible for these inhibitory functions. We find that inhibition is due to two different sets of molecules: (i) the extracellular matrix (ECM) and other surface proteins of the fibroblasts, which are responsible for contact-dependent inhibition of tumor cell proliferation; and (ii) soluble factors secreted by fibroblasts when confronted with tumor cells (confronted conditioned media, CCM) contribute to inhibition of tumor cell proliferation and motility. However, conditioned media (CM) obtained from fibroblasts alone (nonconfronted conditioned media, NCM) did not inhibit tumor cell proliferation and motility. In addition, quantitative PCR (Q-PCR) data show upregulation of proinflammatory genes. Moreover, comparison of CCM and NCM with an antibody array for 507 different soluble human proteins revealed differential expression of growth differentiation factor 15, dickkopf-related protein 1, endothelial-monocyteactivating polypeptide II, ectodysplasin A2, Galectin-3, chemokine (C-X-C motif) ligand 2, Nidogen1, urokinase, and matrix metalloproteinase 3.tumor microenvironment | cancer-associated fibroblast | motility | extracellular matrix | soluble factors T he normal balance between epithelial cells and the surrounding stroma is disrupted during tumor development. Developing preneoplastic cells in the process of escaping from their intrinsic checkpoints that prevent illegitimate cell proliferation also have to overcome the microenvironmental forces that maintain the integrity of the normal tissue architecture. It is becoming increasingly clear that the normal microenvironment can restrict cancer development and progression (1-3). Inhibition of tumor cell growth by normal fibroblasts is one measurable manifestation of this multicomponential control. Part of this process is reflected by the ability of the tumor cell to corrupt the surrounding stroma and turn it from restrictive to supportive. The generation of cancer-associated fibroblasts (CAFs) that enhance angiogenesis and support tumor growth and spreading through the release of growth factors and cytokines is a case in point (1-5).We have departed from the observation of Stoker et al. that normal fibroblasts can inhibit the growth of admixed tumor cells upon contact (6). Having confirmed their findings, we have extended such findings into a high throughput microwell system and showed that the strength of the inhibition differs depending on the source of the fibroblasts. Moreover, such inhibition is contact dependent as well as requires an intact fibroblast monolayer (7, 8).Here we report the surprising finding that the inhi...

show abstract

Section: Discussionsupporting

confidence: 92%

Inhibition of tumor cell proliferation and motility by fibroblasts is both contact and soluble factor dependent

Alkasalias

Flaberg

Kashuba

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Stromal cells, a crucial component of the tumors milieu, are a major source of inflammatory mediators. 5,12,34 Here, we found that in breast CAF and in normal mammary gland fibroblasts (NF), NRs agonists downregulate NF-kBLuc and IL6Luc promoter activity (Figure 4a). In CAF, NRs agonists reduce the expression of a variety of inflammatory cytokines that promote MS formation, [5][6][7][8][9][10][11][12] namely IL6, IL8 and TNFa (Figure 4b).…”

Section: Effects Of Nuclear Receptors On Breast Cancer Stem Cells a Pmentioning

confidence: 74%

“…[5][6][7][9][10][11][12]34 Stromal cells are crucial components of the tumors milieu and are a major source of inflammatory mediators. 5,12,34 Here, we are able to show an NRs dependent downregulation of pro-inflammatory cytokines expression in CAF, and a concomitant reduction of their capability to sustain MS formation. Our data therefore suggest that the in vivo action of NRs on CSCs may involve a co-operative effect of their anti-inflammatory activity on tumor stroma.…”

Section: Discussionmentioning

confidence: 99%

Nuclear receptors agonists exert opposing effects on the inflammation dependent survival of breast cancer stem cells

et al. 2012

View full text Add to dashboard Cite

Recent literature highlights the importance of pro-inflammatory cytokines in the biology of breast cancer stem cells (CSCs), unraveling differences with respect to their normal counterparts. Expansion of mammospheres (MS) is a valuable tool for the in vitro study of normal and cancer mammary gland stem cells. Here, we expanded MSs from human breast cancer and normal mammary gland tissues, as well from tumorigenic (MCF7) and non-tumorigenic (MCF10) breast cell lines. We observed that agonists for the retinoid X receptor (6-OH-11-O-hydroxyphenanthrene), retinoic acid receptor (all-trans retinoic acid (RA)) and peroxisome proliferator-activated receptor (PPAR)-c (pioglitazone (PGZ)), reduce the survival of MS generated from breast cancer tissues and MCF7 cells, but not from normal mammary gland or MCF10 cells. This phenomenon is paralleled by the hampering of pro-inflammatory Nuclear Factor-jB (NF-jB)/Interleukin-6 (IL6) axis that is hyperactive in breast cancer-derived MS. The hindrance of such pathway associates with the downregulation of MS regulatory genes (SLUG, Notch3, Jagged1) and with the upregulation of the differentiation markers estrogen receptor-a and keratin18. At variance, the PPARa agonist Wy14643 promotes MS formation, upregulating NF-jB/IL6 axis and MS regulatory genes. These data reveal that nuclear receptors agonists (6-OH-11-O-hydroxyphenanthrene, RA, PGZ) reduce the inflammation dependent survival of breast CSCs and that PPARa agonist Wy14643 exerts opposite effects on this phenotype.

show abstract

“…Most of the studies have demonstrated that fibroblasts-derived matrix metalloproteinases 26 and cytokines such as vascular endothelial growth factor, 8 stromal cell-derived factor-1, 9 and IL-6, 7 enhanced epithelial tumor growth and progression by using tumor transplantation models. However, whether the results are unique for transplanted tumors is not clear.…”

Section: Discussionmentioning

confidence: 99%

“…Several factors secreted by fibroblasts, such as epidermal growth factor, hepatocyte growth factor, and interleukin-6 (IL-6), can stimulate cancer cell proliferation and enhance their invasive properties. 6,7 Others, such as vascular endothelial growth factor, stromal cell-derived factor-1, and matrix metalloproteinases, can promote angiogenesis. 8 -10 Fibroblast-derived cytokine IL-1 and chemokine (C-X-C motif) ligand 14 have been shown to play vital roles as immune modulators.…”

mentioning

confidence: 99%

FSP1+ Fibroblasts Promote Skin Carcinogenesis by Maintaining MCP-1-Mediated Macrophage Infiltration and Chronic Inflammation

Zhang

Chen

Xiao

et al. 2011

The American Journal of Pathology

View full text Add to dashboard Cite

Cancer development is often associated with increased fibroblast proliferation and extensive fibrosis; however, the role of fibroblasts during carcinogenesis remains largely unknown. Using the 7,12-dimethylbenz-(a)anthracene and 12-O-tetradecanoylphorbol-13-acetateinduced two-stage skin carcinogenesis model, we demonstrated here that there was a massive accumulation and proliferation of fibroblasts in the skin shortly after application of carcinogen. Selective abatement of these cells during the promotion stage drastically decreased incidence and progression of papillomas. This correlated well with reduced macrophage infiltration and impaired cytokine storm in the affected skin. 12-O-tetradecanoylphorbol-13-acetate stimulated skin fibroblasts, secreting high levels of monocyte chemotactic protein-1, and neutralization of this chemokine eliminated almost completely the fibroblast-induced chemotaxis of macrophages. These results strongly suggest that fibroblasts promote skin tumor development by producing monocyte chemotactic protein-1 and maintaining chronic inflammation.

show abstract

Fibroblasts Isolated from Common Sites of Breast Cancer Metastasis Enhance Cancer Cell Growth Rates and Invasiveness in an Interleukin-6–Dependent Manner

Cited by 207 publications

References 50 publications

Inhibition of tumor cell proliferation and motility by fibroblasts is both contact and soluble factor dependent

Inhibition of tumor cell proliferation and motility by fibroblasts is both contact and soluble factor dependent

Nuclear receptors agonists exert opposing effects on the inflammation dependent survival of breast cancer stem cells

FSP1+ Fibroblasts Promote Skin Carcinogenesis by Maintaining MCP-1-Mediated Macrophage Infiltration and Chronic Inflammation

Contact Info

Product

Resources

About