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FSP1 Fibroblasts Promote Skin Carcinogenesis by Maintaining The American Journal of Pathology, Vol. 178, No. 1, January 2011 Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved. DOI: 10.1016/j.ajpath.2010.11.017 Tumorigenesis and Neoplastic Progression FSP1ϩ Fibroblasts Promote Skin Carcinogenesis by Maintaining MCP-1-Mediated Macrophage Infiltration and Chronic Inflammation Jinhua Zhang,*† Lin Chen,*†‡ Mingjie Xiao,*† growth factor, hepatocyte growth factor, and interleukin-6 Chunhui Wang,*†‡ and Zhihai Qin*† (IL-6), can stimulate cancer cell proliferation and en- hance their invasive properties.6,7 Others, such as vas- From the National Laboratory of Biomacromolecules,* and the cular endothelial growth factor, stromal cell-derived fac- China-Japan Joint Laboratory of Structural Virology and † tor-1, and matrix metalloproteinases, can promote Immunology, Institute of Biophysics, Chinese Academy of angiogenesis.8–10 Fibroblast-derived cytokine IL-1 and Sciences, Beijing; and the Graduate School of the Chinese ‡ chemokine (C-X-C motif) ligand 14 have been shown to Academy of Sciences, Beijing, China play vital roles as immune modulators.11,12 Most of these studies, however, came from tumor transplantation ex- periments, which focus mainly on the role of fibroblasts Cancer development is often associated with increased during the growth of transplanted tumor cells. The phys- fibroblast proliferation and extensive fibrosis; however, iological role of fibroblasts and the corresponding molec- the role of fibroblasts during carcinogenesis remains ular mechanisms during chemical carcinogenesis is largely unknown. Using the 7,12-dimethylbenz-(a)an- largely unknown. thracene and 12-O-tetradecanoylphorbol-13-acetate– The 7,12-dimethylbenz-(a)anthracene/12-O-tetradec- induced two-stage skin carcinogenesis model, we anoylphorbol-13-acetate (DMBA/TPA)–induced two-stage demonstrated here that there was a massive accumu- skin carcinogenesis serves as a well-characterized in vivo lation and proliferation of fibroblasts in the skin mouse model for inflammation-induced epithelial neopla- shortly after application of carcinogen. Selective sia, and it mimics the multistage nature of human cancer 13 abatement of these cells during the promotion stage development. A single application of DMBA induces drastically decreased incidence and progression of DNA mutations in epidermal cells and causes tumor ini- papillomas. This correlated well with reduced macro- tiation. Promotion requires repeated exposure of the skin phage infiltration and impaired cytokine storm in the to TPA, which boosts tumor development via induction of 14 affected skin. 12-O-tetradecanoylphorbol-13-acetate chronic inflammation. Considering the fact that most of stimulated skin fibroblasts, secreting high levels of human neoplasias are of epithelial origin, and 20% of the cancers are clearly associated with chronic inflamma- monocyte chemotactic protein-1, and neutralization 15–17 of this chemokine eliminated almost completely the tion, it is interesting to analyze the role of fibroblasts during skin carcinogenesis with the well established fibroblast-induced chemotaxis of macrophages. DMBA/TPA model. These results strongly suggest that fibroblasts pro- For this purpose, FSP-TK transgenic mice were used, mote skin tumor development by producing mono- in which the expression of herpes simplex virus–derived cyte chemotactic protein-1 and maintaining chronic inflammation. (Am J Pathol 2011, 178:382–390; DOI: 10.1016/j.ajpath.2010.11.017) Supported by the National Natural Science Foundation of China (81030049, 30700287 and 31071261) and the Ministry of Science and Technology of China (2009CB918901). It has been noted putatively that distinct cellular changes J.Z and L.C. contributed equally to this work. 1,2 in the microenvironment accompany tumor formation. Accepted for publication September 21, 2010. Increased fibroblast proliferation is often observed adja- None of the authors disclosed any relevant financial relationships. cent to cancer cells. For example, cancers of lung, liver, Supplemental material for this article can be found at http://ajp. and breast are often associated with fibroblast activation, amjpathol.org or at doi: 10.1016/j.ajpath.2010.11.017. 3–5 proliferation, and collagen deposition. Fibroblasts may Address reprint requests to Zhihai Qin, M.D., Institute of Biophysics, influence cancer development in different ways. Several Chinese Academy of Sciences, 15 Datun Rd., Beijing 100101, China. factors secreted by fibroblasts, such as epidermal E-mail: [email protected]. 382 Fibroblasts Promote Skin Carcinogenesis 383 AJP January 2011, Vol. 178, No. 1 thymidine kinase (TK) was expressed under the control of Hyperplasia and Immunohistochemistry the promoter of a fibroblast-specific gene fibroblast spe- cific protein-1 (FSP1).18–20 With activation of the “suicide” Preparation of cryostat or paraffin tissue sections and im- 23 gene TK, the phosphorylated products of ganciclovir munohistochemistry were done as described previously. (GCV)21 are able to deplete the proliferating FSP1ϩ cells The thickness of the epidermis (in micrometers) was in vivo selectively. In the current study, we showed for the measured with an image system (Photoshop; Adobe Sys- first time that depletion of proliferating fibroblasts during tems Inc., San Jose, CA) and calculated as following: the the tumor promotion stage decreased the incidence and actual thickness of epidermis ϭ on-screen measure- number of papillomas as well as their malignant conver- ments of epidermis/magnification (10 fields per section). sion rate. Furthermore, fibroblasts influenced skin carci- For FSP1 staining, paraffin sections were incubated with nogenesis by direct production of MCP-1 and up-regu- rabbit anti-FSP1 polyclonal antibodies (a gift from Dr. Eric lation of local inflammation. G. Neilson), then incubated with biotinylated secondary antibody followed by streptavidin-peroxidase. The perox- idase activity was detected with diaminobenzidine (DAB; Materials and Methods Sigma) and the sections were counterstained with hema- toxylin. For proliferating cell nuclear antigen (PCNA), ␣ Mice smooth muscle actin (␣-SMA), F4/80 and CD11b detec- tion, paraffin or frozen sections were incubated with anti- BALB/c mice were purchased from Weitonglihua Corpo- PCNA (Sigma), anti-␣-SMA (Abcam), anti-F4/80 (eBio- ration (Beijing, China). FSP-TK transgenic mice and wild- science, San Diego, CA), and anti-CD11b (BD Pharmingen) type control littermates were obtained from Dr. Eric G. monoclonal antibodies respectively. Then biotinylated Neilson’s lab. All mice were bred under specific patho- secondary antibody and Rhodamine-labeled streptavidin gen-free conditions in the animal facilities at the Institute were used. Sections were counterstained with 4,6-dia- of Biophysics, Chinese Academy of Sciences. All animal midino-2-phenylindole (DAPI; Sigma). For FSP1 and studies were performed with sex- and age-matched mice Ki-67 double labeling, paraffin sections were incubated after being approved by the Institutional Laboratory Ani- with a mixture of rabbit anti-FSP1 and mouse anti-Ki-67 mal Care and Use Committee. (BD Pharmingen) antibodies followed by the mixture of Rhodamine-labeled goat anti-rabbit IgG and fluorescein Skin Carcinogenesis and GCV Treatment isothiocyanate (FITC)–labeled horse anti-mouse IgG. For FSP1 and ␣-SMA double labeling, paraffin sections were Groups of FSP-TK mice and control littermates were sub- incubated with a mixture of rabbit anti-FSP1 and mouse jected to a single topical application of 50 ␮g DMBA anti-␣-SMA antibodies followed by the mixture of FITC- (Sigma), and 1 week later, 4 ␮g TPA (Sigma) twice a labeled goat anti-rabbit IgG and Rhodamine-labeled week for 14 weeks. To deplete proliferating fibroblasts, horse anti-mouse IgG. For cytokeratin (CK) and PCNA 0.5 mg GCV (HuBeiKeYi Pharmaceutic Corporation) dis- double labeling, paraffin sections were incubated with a solved in acetone was given 0.5 hours after TPA admin- mixture of rabbit anti-CK (Abcam) and mouse anti-PCNA istration. Mice were divided into the following groups: (1) antibodies followed by the mixture of FITC-labeled goat FSP-TK mice treated with DMBA, TPA, and GCV in ace- anti-rabbit IgG and Rhodamine-labeled horse anti-mouse tone; (2) FSP-TK mice treated with DMBA, TPA, and ac- IgG. Sections were evaluated under the microscope etone alone; (3) control littermates treated with DMBA, (DP71, Olympus) for bright-field and fluorescence mi- TPA, and GCV in acetone; and (4) control littermates croscopy. treated with DMBA, TPA, and acetone alone. After shaving a 2-cm2 area of the dorsal skin, DMBA, Cytokine Determination TPA, or GCV that was dissolved in 100 ␮l acetone was administered by a micropipette. The area was regularly For detection of cytokines in skin tissues, dorsally shaved shaved and tumors of Ն1 mm in diameter, which had TPA-treated skins were homogenized in ice-cold TE been present for at least 2 weeks, were assessed twice buffer. Homogenates were centrifuged at 12,000Xg for 15 per week. Papillomas were evaluated as typically well minutes. The supernatant was collected and the levels of demarcated, symmetrical, pedunculated, or dome-shaped IL-6, MCP-1, interferon-␥ (IFN-␥), tumor necrosis factor-␣ papules without erosion or ulceration. Carcinomas were (TNF-␣), IL-10, and IL-12p70 were assayed by a Mouse scored as poorly demarcated, asymmetrical, nonpedun- Inflammation Cytometric Bead Array (CBA) Kit (BD Phar- culated, or dome-shaped
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