CXCL14 is an autocrine growth factor for fibroblasts and acts as a multi-modal stimulator of prostate tumor growth

Augsten, Martin; Hägglöf, Christina; Olsson, Elin; Stolz, Claudia; Tsagozis, Panagiotis; Levchenko, Tetyana; Frederick, Mitchell J.; Borg, Åke; Micke, Patrick; Egevad, Lars; Östman, Arne

doi:10.1073/pnas.0813144106

Cited by 209 publications

(234 citation statements)

References 26 publications

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“…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: 82%

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.

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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...

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Section: Discussionsupporting

confidence: 82%

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.

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“…These observations were supported by in vivo data: in a mouse model of transplantable mammary carcinoma, CAF-secreted CCL2 recruited macrophages into mammary tumours and specific ablation of CCL2 reduced tumour metastasis [65]. Other CAF-derived chemokines were also reported to enhance macrophage recruitment to various tumours: Augsten et al reported that prostate CAFs up-regulate CXCL14 that functioned to promote macrophage migration into prostate cancer xenografts [66]. Inhibition of NF-κB signalling, driving expression of CXCL1 and CXCL2 in skin CAFs, resulted in decreased macrophage infiltration into transplanted skin tumours and reduced tumour growth, indicating a central role for CAFs in facilitating the trafficking of macrophages into tumours [39].…”

Section: Activation By Paracrine Signallingmentioning

confidence: 82%

From sentinel cells to inflammatory culprits: cancer‐associated fibroblasts in tumour‐related inflammation

Servais

Erez

2012

The Journal of Pathology

133

113

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“…In vitro co-culture of macrophages with tumor cells has been shown to result in accelerated tumor growth [49]. TAMs express several factors, such as EGF, MMP-9, TGF-β and CXCL-14, that stimulate tumor cell proliferation and survival [50,51]. However, it is unclear whether macrophage density in tumor stroma is directly linked to tumor demography.…”

Section: Discussionmentioning

confidence: 99%

Macrophage Infiltration in Tumor Stroma is Related to Tumor Cell Expression of CD163 in Colorectal Cancer

Shabo

Olsson

Elkarim

et al. 2014

Cancer Microenvironment

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The scavenger receptor, CD163, is a macrophagespecific marker. Recent studies have shown that CD163 expression in breast and rectal cancer cells is associated with poor prognosis. This study was conducted to evaluate the relationship between CD163 expression as a macrophage trait in cancer cells, and macrophage infiltration and its clinical significance in colorectal cancer. Immunostaining of CD163 and macrophage infiltration were evaluated in paraffinembedded specimens, earlier analyzed for CD31, D2-40 and S-phase fraction, from primary tumors and normal colorectal mucosa of 75 patients with colorectal carcinoma. The outcomes were analyzed in relation to clinical-pathological data. CD163 expression was positive in cancer cells in 20 % of colorectal cancer patients and was related to advanced tumor stages (P=0.008) and unfavorable prognosis (p=0.001). High macrophage infiltration was related to shorter survival and positive CD163 expression in tumor cells. The prognostic impact of macrophage infiltration was independent of tumor stage and CD163 expression in cancer cells (p=0.034). The expression of macrophage phenotype in colorectal cancer cells is associated with macrophage density in tumor stroma and lower survival rates. Macrophage infiltration has an independent prognostic impact on mortality in colorectal cancer. In accordance with previous experimental studies, these findings provide new insights into the role of macrophages in colorectal cancer.

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CXCL14 is an autocrine growth factor for fibroblasts and acts as a multi-modal stimulator of prostate tumor growth

Cited by 209 publications

References 26 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

From sentinel cells to inflammatory culprits: cancer‐associated fibroblasts in tumour‐related inflammation

Macrophage Infiltration in Tumor Stroma is Related to Tumor Cell Expression of CD163 in Colorectal Cancer

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