Fibroblast-Specific Protein 1/S100A4–Positive Cells Prevent Carcinoma through Collagen Production and Encapsulation of Carcinogens

Zhang, Jinhua; Chen, Lin; Liu, Xiaoman; Kammertoens, Thomas; Blankenstein, Thomas; Qin, Zhihai

doi:10.1158/0008-5472.can-12-3022

Cited by 67 publications

(49 citation statements)

References 45 publications

(60 reference statements)

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“…Those of PDGFRβ type are thought to be associated with metastatic spread [25] and high interstitial fluid pressure [26]. S100A4 (FSP-1)-type CAFs, which were highly expressed in breast cancer with fibrous stroma in our study, have been suggested to associate with metastatic colonization [27], macrophage infiltration [28], and protection from carcinogens [29]. There are several possible explanations for the differential expression of CAFrelated proteins between breast cancer with fibrous and adipose stroma.…”

Section: Discussionmentioning

confidence: 58%

Expression of cancer-associated fibroblast-related proteins in adipose stroma of breast cancer

2015

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Cancer-associated fibroblasts (CAFs) play key roles in tumor microenvironment; they are thought to originate from adipocytes. This study aimed to evaluate CAF-related protein expression and its implications in breast cancer. Of the 939 enrolled breast cancer patients, 642 had fibrous and 297 had adipose stroma. The status of estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 (HER-2), Ki-67, podoplanin, prolyl 4-hydroxylase, fibroblast activation protein α (FAPα), S100A4, platelet-derived growth factor receptor α (PDGFRα), PDGFRβ, and chondroitin sulfate proteoglycan (NG2) was evaluated via tissue microarrays. Tumors were divided into luminal A, luminal B, HER-2, or triple-negative breast cancer subtypes according to their molecular status. Luminal A subtype was more prevalent in breast cancer of adipose stroma type, whereas other molecular subtypes were more common in fibrous stroma type (p < 0.001). Tumor cell expression of podoplanin and FAPα was higher in adipose stroma type, while higher expression of prolyl 4-hydroxylase and PDGFRα was observed in fibrous stroma type. Furthermore, adipose stroma type exhibited higher stromal expression of podoplanin, FAPα, PDGFRβ, and NG2, whereas fibrous stroma type had higher prolyl 4-hydroxylase and S100A4 expression. In adipose stroma type, tumor positivity (p = 0.034) and stromal positivity (p = 0.005) of prolyl 4-hydroxylase were associated with shorter disease-free survival, and stromal prolyl 4-hydroxylase positivity was with shorter overall survival (p < 0.001). In conclusion, expression of CAF-related proteins was observed in breast cancer, with different profiles between adipose and fibrous stroma types. Prolyl 4-hydrolase status might be of prognostic value in adipose stroma type.

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Section: Discussionmentioning

confidence: 58%

Expression of cancer-associated fibroblast-related proteins in adipose stroma of breast cancer

2015

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“…S100A4, also known as fibroblast-specific protein 1, is a member of the S100 calcium-binding protein family and was first cloned in metastatic cells and fibroblasts [13,14]. It is expressed in various cell types, including fibroblasts, macrophages and tumor cells [15][16][17][18][19][20]. S100A4 was reported to be intracellular, or secreted as a normal cytokine, and it plays important roles in tumor cell survival and metastasis [19,21,22].…”

Section: Introductionmentioning

confidence: 99%

S100A4 protects mice from high-fat diet-induced obesity and inflammation

Hou

Jiao

et al. 2018

Laboratory Investigation

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As a member from S100 calcium-binding protein family, S100A4 is ubiquitous and elevated in tumor progression and metastasis, but its role in regulating obesity has not been well characterized. In this study, we showed that S100A4 was mainly expressed by stromal cells in adipose tissue and the S100A4 level in adipose tissue was decreased after high-fat diet (HFD). S100A4 deficient mice exhibited aggravated symptoms of obesity and suppressed insulin signaling after 12 weeks of HFD. Aggravated obesity in S100A4 deficient mice were found to be positively correlated with higher inflammatory status of the liver. Then, we found that extracellular S100A4 or overexpressed S100A4 inhibited adipogenesis and decreased mRNA levels of inflammation gene in 3T3-L1 adipocytes in vitro; whereas small interfering RNA (siRNA)-mediated suppression of S100A4 displayed the opposite results. Additionally, the protective effect induced by S100A4 during HFD-induced obesity was tightly related with activation of Akt signaling in adipose tissues, as well as livers and muscles. Taken together, we demonstrate that S100A4 is an inhibitory factor for obesity and attenuates the inflammatory reaction, while activating the Akt signaling, which suggest that S100A4 is a potential candidate for the treatment of diet-induced obesity and its complications.

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“…17 , 18 Previous studies have reported that S100A4 is expressed in a variety of cells, such as fibroblasts, macrophages, and malignant cells, and plays a crucial role in mediating tumor-stromal interplay. 19-23 S100A4 functions as both intracellular and extracellular forms. 24 , 25 Intracellular S100A4 is involved in a wide range of biological functions, such as the regulation of angiogenesis, cell survival, motility, invasion or metastasis.…”

Section: Introductionmentioning

confidence: 99%

S100A4 promotes colon inflammation and colitis-associated colon tumorigenesis

Zhang

Hou

et al. 2018

OncoImmunology

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S100A4 plays important roles in tumor development and metastasis, but its role in regulating inflammation and colitis-associated tumorigenesis has not been well characterized. Here, we report that S100A4 expression was increased in azoxymethane (AOM) and dextran sulfate sodium (DSS) induced colorectal cancer (CRC) in mice. After AOM/DSS treatment, both S100A4-TK mice with the selective depletion of S100A4-expressing cells and S100A4-deficient (S100A4−/−) mice developed fewer and smaller tumors than wild-type (WT) control littermates. Furthermore, S100A4−/− mice were resistant to DSS-induced colitis, reduced infiltration of macrophages, and the diminished production of proinflammatory cytokines. Further studies revealed that reduced colon inflammation and colorectal tumor development in S100A4−/− mice were partly due to the dampening of nuclear factor (NF)-κB activation in macrophages. Furthermore, the administration of a neutralizing S100A4 antibody to WT mice significantly decreased AOM/DSS-induced colon inflammation and tumorigenesis. These results indicate that S100A4 amplifies an inflammatory microenvironment that promotes colon tumorigenesis and provides a promising therapeutic strategy for treatment of inflammatory bowel disease and prevention of colitis-associated colorectal carcinogenesis.

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Fibroblast-Specific Protein 1/S100A4–Positive Cells Prevent Carcinoma through Collagen Production and Encapsulation of Carcinogens

Cited by 67 publications

References 45 publications

Expression of cancer-associated fibroblast-related proteins in adipose stroma of breast cancer

Expression of cancer-associated fibroblast-related proteins in adipose stroma of breast cancer

S100A4 protects mice from high-fat diet-induced obesity and inflammation

S100A4 promotes colon inflammation and colitis-associated colon tumorigenesis

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