Functional subsets of mesenchymal cell types in the tumor microenvironment

Cortez, Eliane; Roswall, Pernilla; Pietras, Kristian

doi:10.1016/j.semcancer.2013.12.010

Cited by 99 publications

(93 citation statements)

References 76 publications

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“…In line with these results, we found that mPGES-1 + cells in all three tumors analyzed (NB1, NB4, and NB43) expressed one or more markers for CAFs. The MYCN-amplified tumor NB1 coexpressed mPGES-1 and CAF markers such as vimentin, FAP, αSMA, and PDGFRβ but not FSP-1 and PDGFRα (41). Although mPGES-1 + cells in NB4 expressed vimentin, PDGFRα, PDGFRβ, and FSP-1, no colocalization with FAP or αSMA was detected.…”

Section: Discussionmentioning

confidence: 94%

COX/mPGES-1/PGE ₂ pathway depicts an inflammatory-dependent high-risk neuroblastoma subset

Larsson

Kock

Idborg

et al. 2015

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

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The majority of solid tumors are presented with an inflammatory microenvironment. Proinflammatory lipid mediators including prostaglandin E 2 (PGE 2 ) contribute to the establishment of inflammation and have been linked to tumor growth and aggressiveness. Here we show that high-risk neuroblastoma with deletion of chromosome 11q represents an inflammatory subset of neuroblastomas. Analysis of enzymes involved in the production of proinflammatory lipid mediators showed that 11q-deleted neuroblastoma tumors express high levels of microsomal prostaglandin E synthase-1 (mPGES-1) and elevated levels of PGE 2 . High mPGES-1 expression also corresponded to poor survival of neuroblastoma patients. Investigation of the tumor microenvironment showed high infiltration of tumor-promoting macrophages with high expression of the M2-polarization markers CD163 and CD206. mPGES-1-expressing cells in tumors from different subtypes of neuroblastoma showed differential expression of one or several cancer-associated fibroblast markers such as vimentin, fibroblast activation protein α, α smooth muscle actin, and PDGF receptor β. Importantly, inhibition of PGE 2 production with diclofenac, a nonselective COX inhibitor, resulted in reduced tumor growth in an in vivo model of 11q-deleted neuroblastoma. Collectively, these results suggest that PGE 2 is involved in the tumor microenvironment of specific neuroblastoma subgroups and indicate that therapeutic strategies using existing anti-inflammatory drugs in combination with current treatment should be considered for certain neuroblastomas.

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Section: Discussionmentioning

confidence: 94%

COX/mPGES-1/PGE ₂ pathway depicts an inflammatory-dependent high-risk neuroblastoma subset

Larsson

Kock

Idborg

et al. 2015

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

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“…Recently, Cortez and colleagues divided the heterogeneous population of CAFs in four discrete, markerbased CAF subsets characterized by either aSMA (Acta2), FSP1, PDGFR-a, or PDGFR-b expression, respectively. (17). FSP1-expressing CAFs (CAF FSP1 ) are characterized by VEGFA and Tenascin C expression, and have been shown to promote the recruitment of macrophages into the tumor (18,40).…”

Section: Discussionmentioning

confidence: 99%

“…S6A). Fsp1 has been proposed as a marker of a functionally discrete CAF subtype (17). The expression level of tenascin C (Tnc), previously shown to be associated with the Fsp1-positive CAF subtype (18), was also enhanced in NIH-CXCL14 compared with NIH-ctr cells.…”

Section: Induction Of Nos1 Expression Is a Consequence Of Oxidative Smentioning

confidence: 99%

Cancer-Associated Fibroblasts Expressing CXCL14 Rely upon NOS1-Derived Nitric Oxide Signaling for Their Tumor-Supporting Properties

et al. 2014

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Cancer-associated fibroblasts (CAF) stimulate tumor growth and metastasis. Signals supporting CAF function are thus emerging as candidate therapeutic targets in the tumor microenvironment. The chemokine CXCL14 is a potent inducer of CAF protumorigenic functions. This study is aimed at learning how the protumoral functions of CXCL14-expressing CAF are maintained. We found that the nitric oxide synthase NOS1 is upregulated in CXCL14-expressing CAF and in fibroblasts stimulated with CXCL14. Induction of Nos1 was associated with oxidative stress and occurred together with activation of NRF2 and HIF1a signaling in CXCL14-expressing CAF. Genetic or pharmacologic inhibition of NOS1 reduced the growth of CXCL14-expressing fibroblasts along with their ability to promote tumor formation following coinjection with prostate or breast cancer cells. Tumor analysis revealed reduced macrophage infiltration, with NOS1 downregulation in CXCL14-expressing CAF and lymphangiogenesis as a novel component of CXCL14-promoted tumor growth. Collectively, our findings defined key components of a signaling network that maintains the protumoral functions of CXCL14-stimulated CAF, and they identified NOS1 as intervention target for CAF-directed cancer therapy. Cancer Res; 74(11); 2999-3010. Ó2014 AACR.

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“…For example, FSP1 and PDGFRa are also expressed in normal fibroblasts or other cell types (9,10). In contrast, FAP is selectively expressed by CAFs in most of human epithelial cancers as well as by reactive stromal fibroblasts under some inflammatory conditions, such as liver cirrhosis (11,12).…”

Section: Introductionmentioning

confidence: 99%

FAP Promotes Immunosuppression by Cancer-Associated Fibroblasts in the Tumor Microenvironment via STAT3–CCL2 Signaling

et al. 2016

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Cancer-associated fibroblasts (CAF) are components of the tumor microenvironment whose contributions to malignant progression are not fully understood. Here, we show that the fibroblast activation protein (FAP) triggers induction of a CAF subset with an inflammatory phenotype directed by STAT3 activation and inflammation-associated expression signature marked by CCL2 upregulation. Enforcing FAP expression in normal fibroblasts was sufficient to endow them with an inflammatory phenotype similar to FAP þ CAFs. We identified FAP as a persistent activator of fibroblastic STAT3 through a uPAR-dependent FAK-Src-JAK2 signaling pathway. In a murine liver tumor model, we found that FAP þ CAFs were a major source of CCL2 and that fibroblastic STAT3-CCL2 signaling in this setting promoted tumor growth by enhancing recruitment of myeloid-derived suppressor cells (MDSC). The CCL2 receptor CCR2 was expressed on circulating MDSCs in tumor-bearing subjects and FAP þ CAF-mediated tumor promotion and MDSC recruitment was abrogated in Ccr2-deficient mice. Clinically, we observed a positive correlation between stromal expression of FAP, p-STAT3, and CCL2 in human intrahepatic cholangiocarcinoma, a highly aggressive liver cancer with dense desmoplastic stroma, where elevated levels of stromal FAP predicted a poor survival outcome. Taken together, our results showed how FAP-STAT3-CCL2 signaling in CAFs was sufficient to program an inflammatory component of the tumor microenvironment, which may have particular significance in desmoplasia-associated cancers. CancerRes; 76(14); 4124-35. Ó2016 AACR.

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Functional subsets of mesenchymal cell types in the tumor microenvironment

Cited by 99 publications

References 76 publications

COX/mPGES-1/PGE ₂ pathway depicts an inflammatory-dependent high-risk neuroblastoma subset

COX/mPGES-1/PGE ₂ pathway depicts an inflammatory-dependent high-risk neuroblastoma subset

Cancer-Associated Fibroblasts Expressing CXCL14 Rely upon NOS1-Derived Nitric Oxide Signaling for Their Tumor-Supporting Properties

FAP Promotes Immunosuppression by Cancer-Associated Fibroblasts in the Tumor Microenvironment via STAT3–CCL2 Signaling

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Functional subsets of mesenchymal cell types in the tumor microenvironment

Cited by 99 publications

References 76 publications

COX/mPGES-1/PGE 2 pathway depicts an inflammatory-dependent high-risk neuroblastoma subset

COX/mPGES-1/PGE 2 pathway depicts an inflammatory-dependent high-risk neuroblastoma subset

Cancer-Associated Fibroblasts Expressing CXCL14 Rely upon NOS1-Derived Nitric Oxide Signaling for Their Tumor-Supporting Properties

FAP Promotes Immunosuppression by Cancer-Associated Fibroblasts in the Tumor Microenvironment via STAT3–CCL2 Signaling

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COX/mPGES-1/PGE ₂ pathway depicts an inflammatory-dependent high-risk neuroblastoma subset

COX/mPGES-1/PGE ₂ pathway depicts an inflammatory-dependent high-risk neuroblastoma subset