Overview and rationale - 細胞激素受體 IL-17RB 與乳腺脂肪細胞在乳癌癌化過程中所扮演之角色

Breast cancer

Breast cancer is one of the malignant diseases leading to cell death in women worldwide. In 2015, there will be an estimated 231,840 new cancer cases diagnosed and 40,290 cancer deaths in the United States. Although the incidence of breast caner is declined during the last decade, it remains the first and second in cancer incidence and death rate in the United States, respectively (Siegel et al., 2015). Compared to the United States, the incidence of breast cancer in Taiwan is constantly increased since 1979 to 2011. (Statistics form Health Promotion Administration, Ministry of Health and Welfare, Taiwan. Download is available at http://www.hpa.gov.tw). It ranks first and fourth in frequency for both diagnosis and cause of death in Taiwan women, respectively (Fig. I-1).

Based on the gene expression profiling and immunohistochemistry (IHC), breast cancers can be classified into at least 5 groups: luminal type A&B (both are estrogen receptor positive, ER⁺), HER2 (human epidermal growth factor receptor positive, HER2/neu⁺), basal like (also called triple negative, ER^-/PR^-/HER2^-), and normal breast

Proportion of major cancer incidence, 2011

(8,140)colon 16%

Fig. I-1. Cancer incidence of 10 common cancers in Taiwan, 2011 Adapted from http://www.hpa.gov.tw

like (Fig. I-2a)(Vargo-Gogola and Rosen, 2007). Each subtype of breast cancer shows different risk factors of incidence, treatment response, and even disease progression risk.

Among these different types of breast cancer, overexpression of nuclear receptor ER and membrane bound receptor HER2/neu protein accounts for approximate 85% of breast cancer. Compared to luminal ER⁺ breast cancer, the basal type and HER2/neu⁺ breast cancers exhibit high malignancy and poor prognosis (Fig. I-2b).

Fortunately, the development of hormone and targeting therapy (Tamoxifen and Trastuzumab, also called Herceptin) for ER⁺ and HER2⁺ breast cancer treatment significantly improve the clinical outcomes, respectively. However, development of drug resistance, limited response rate, and cancer recurrence remain to be resolved. Thus, identification of novel pathways involved in breast cancer tumorigenesis is urgently needed to offer new targets for developing the corresponding treatments.

Nature Reviews | Cancer Luminal

subtype A Luminal

subtype B ERBB2⁺ Normal

breast-like An experimental method for estimating the number of cells that have stem or progenitor or tumour-initiating behaviour within a population of cells.

Aldefluor

An aldehyde dehydrogenase (ALDH) substrate that allows the identification and isolation of stem or progenitor cells based on the observation that these cells have high ALDH

MCF-7 sub-line, MCF-S, forms mammospheres, exhibits the CD44⁺CD24^– expression profile and is enriched by 1000-fold in tumour-initiating capacity compared with the parental cells¹⁹. Other laboratories have examined subpopulations of MCF-7 cells that demonstrate reduced sensitivity to radiation and enhanced self-renewal capabilities in mammosphere assays^26–28. However, the tumour-initiating capability of these subpopulations was not reported.

Recently, Kuperwasser and colleagues tested the tumour-initiating potential of CD44⁺CD24^– populations within breast cancer cell lines directly by performing limiting dilution transplantation experiments. These markers did not correlate with tumour-initiating capability, but instead were indicative of a basal subtype (C. Kuperwasser and C. Fillmore, personal communication). However, an ESA⁺ fraction within the CD44⁺CD24^– subpopulation showed enrichment for tumour-initiating capability and

Is the expression of CD44⁺CD24^–ESA⁺ markers broadly indicative of tumour-initiating subpopulations within cell lines? Accumulating evidence suggests that their expression is heterogeneous within cell lines and breast cancers^19,29–31. Furthermore, their relationship to clinical outcome is unclear^30–32. More functional studies (using limiting dilution transplantation of cells isolated by FACS (fluorescent activated cell sorting)) that utilize the different subtypes of breast cancer are required to conclude definitively whether each subtype contains subpopulations of tumour-initiating cells and whether they display identical or distinct cell surface markers.

Improved methods and markers are needed to identify and characterize tumour-initiating cells within cell lines and breast cancers. One promising approach may be to use the stem cell marker ^aldefluor³³ in FACS analy-sis coupled with immunohistochemistry (IHC) using an anti-aldehyde dehydrogenase 1 (ALDH1) antibody (M. Wicha, personal communication). Notwithstanding these limitations, several studies indicate that certain cell lines can be used to investigate the cellular and molecular distinctions between the tumour-initiating and non-tumour-initiating subpopulations19,26,28,34. 2D versus 3D culture conditions. The molecular profil-ing studies described above indicate that cell lines have many of the genetic and genomic alterations found in primary breast cancers. However, most of these studies were performed using cell lines cultured on plastic^12,13,35. A principal limitation of in vitro cell culture studies is that the culture conditions used to propagate these cells create an environment that differs markedly from the breast microenvironment. This caveat must be consid-ered when discussing the fidelity with which cell lines model breast cancer ^{(FIG. 3)}.

Recently, to determine whether gene expression, like morphology, is more faithfully recapitulated in breast can-cer cell lines when grown in 3D reconstituted basement membrane (rBM) cultures, the molecular profiles of 25 breast cancer cell lines cultured in 2D versus 3D conditions were compared³⁶. Not surprisingly, molecular profiles of individual cell lines were more similar to themselves than to other cell lines grown in the same culture conditions, indicating that the 3D culture environment does not pro-mote global changes in gene-expression patterns. However, a group of signal transduction genes were identified that significantly correlated with cells grown in the 3D envi-ronment. Altered expression of these genes coupled with post-transcriptional gene regulation probably accounts for the morphological and behavioural differences of cells grown in 3D compared with 2D cultures³⁷.

Bissell, Brugge and colleagueshave pioneered the 3D culture methods of breast epithelial and tumour cell lines, and readers are directed to a number of excellent reviews on modelling the microenvironment in 3D cultures^38–41. Three-dimensional culture models have been used to investigate the critical signalling pathways that regulate tumour biology. For example, Weaver and colleagues⁴² have demonstrated how one feature of breast cancer biology, stromal rigidity and its effects Figure 2 | The identification of breast cancer subtypes by molecular profiling.

a | The concept that breast cancer is not a single disease is demonstrated by the increasing number of gene-expression profiling studies, which suggest that there are at least five subtypes of invasive ductal carcinoma (IDC) that constitute approximately 80% of all breast cancers^10,131. A dendogram shows clustering of 115 breast tumours into the five subtypes of IDC. Grey branches indicate tumours that did not correlate with any subtype¹³². Invasive lobular carcinomas, which also display distinct gene-expression profiles, constitute an additional 10–15% of breast cancers (not shown)¹³³. Ten additional rare types of breast cancer have also been described, although collectively these account for less than 10% of newly diagnosed cases each year (see the Mayo Clinic web page on breast cancer). b | The prognostic outcomes for each subtype of IDC are shown as overall survival. The ERBB2⁺ and basal subtypes demonstrate the worst prognoses, whereas the luminal subtype A shows the most favourable outcome.

Recently, it has been demonstrated that the prognostic outcomes of the subtypes were not different when a pathologically complete response to therapy was achieved¹³⁴. It has been suggested that the distinct prognostic outcomes between the subtypes may reflect the differential responses of the bulk of the tumour and tumour-initiating cell populations to chemotherapy and targeted therapies¹³⁵. Reproduced with permission from REF. 132 ¢ (2007) National Academy of Sciences, USA.

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Fig. I-2. The identification of breast caner subtypes by molecular profiling.

(a) Breast cancer is heterogeneous that can be classified into at least 5 subtypes according gene expression profiling. (b) The prognostic outcomes for each subtype of invasive breast cancer.

Adapted from Nat Rev Cancer., 7: 659-672, 2007

IL-17 family and tumorigenesis

IL-17 family is a large cytokine family that consists of six IL-17 cytokines and five IL-17R receptors (Fig. I-3). IL-17A and IL-17F, mainly secreted from T helper 17 (TH17) cells, are the most well-characterized members in the IL-17 family (Iwakura et al., 2011). IL-17A can either form homodimer with IL-17A or heterodimer pathway is involved in TH17 cells regulation and production of several pro-inflammatory cytokines. Dysregulation of IL-17A related pathway is associated with many autoimmune diseases (Kirkham et al., 2014). IL-17E (also known as IL-25) is produced by mucosal epithelial cells and many immune cells. It has been reported that IL-17E regulates type-2 immune response and stimulates TH2-type cytokines production (Dong, 2008). However, the function of IL-17B, IL-17C, and IL-17D remain elusive.

Th17 cell development still remains elusive (reviewed inKorn et al., 2009).

The Th17 cell lineage is heterogeneous population. In addition to IL-17A and IL-17F double-positive cells, populations that are only IL-17A or IL-17F positive have been identified. The mecha-nisms that regulate IL-17A and IL-17F production also differ;

IL-17F is expressed earlier than IL-17A during Th17 cell develop-ment (Lee et al., 2009). Although underlying molecular mecha-nisms have not been described, it is likely that several mediators, such as transcription factor or T cell receptor (TCR) signaling, distinctly regulate the production of the cytokines. Indeed, defi-ciency of RORa selectively reduced IL-17A production (Yang et al., 2008b), and IL-17A expression was more sensitive to the strength of TCR signaling (Gomez-Rodriguez et al., 2009).

In addition to Th17 cells, a wide variety of T cells also produce IL-17A and IL-17F. These cytokines are produced by cytotoxic CD8⁺T cells (Tc17) under conditions that are similar to those required by Th17 cells, but different from those required by IFN-g producing CD8⁺T cells (Tc1). Similarly, distinct popula-tions of gdT (gd-17) cells and NKT (NKT-17) cells produce IL-17A and IL-17F (reviewed inCua and Tato, 2010). However, IL-23 and IL-1 can directly induce gd-17 cell development in the absence of IL-6 and TCR ligation because, unlike naive

CD4⁺and CD8⁺T cells, these cells constitutively express IL-23R, IL-1R, and RORgt. Likewise, NKT cells produce IL-17A in the presence of IL-1 and IL-23 in combination with TCR stim-ulation. These two T cell populations (gd-17 and NKT-17) can rapidly produce IL-17A and IL-17F in response to proinflamma-tory cytokine stimulation and may therefore provide an essential initial source of these two cytokines.

More recently, innate lymphoid populations of neutrophils, monocytes, natural killer cells, and lymphoid tissue inducer (LTi)-like cells have been shown capable of rapidly producing IL-17A and IL-17F (Cua and Tato, 2010). In addition, IL-17A is produced by intestinal Paneth cells (Takahashi et al., 2008), whereas IL-17F mRNA, but not IL-17A mRNA, is expressed in colonic epithelial cells (Ishigame et al., 2009), suggesting that IL-17A and IL-17F from nonlymphoid cells may also regulate immune responses. Substantial efforts are underway to clarify the mechanisms that control IL-17A and IL-17F production in these cell types, and the relative contributions of the resulting cytokines in immune responses.

Signaling Mechanism of IL-17A and IL-17F

Both Il17ra^!/!and Il17rc^!/!mice fail to respond to both IL-17A and IL-17F, indicating that both IL-17RA and IL-17RC are Act1

Figure 1. IL-17 and the IL-17 Receptor Families

Six IL-17 family cytokines (IL-17A to IL-17F) and five IL-17R family molecules (IL-17RA to IL-17RE) have been identified. After binding of an IL-17A or IL-17F homodimer or heterodimer to IL-17R (the heterodimer of IL-17RA and IL-17RC), Act1 associates with IL-17RA and/or IL-17RC through its SEFIR domains.

Subsequently, the complex associates with TRAF6, leading to the activation of NF-kB, MAPK-AP-1, and C/EBP. Downstream of IL-17R, TRAF3 also associates with Act1 to inhibit Act1-TRAF6-mediated activation of transcription factors. Act1-independent ERK activation also contributes to IL-17R signaling via an unknown molecule (?). Similar to signaling via IL-17R, IL-17E (IL-25) binding to IL-25R (heterodimer of IL-17RA and IL-17RB) results in activation of NF-kB, MAPK-AP-1, and C/EBP via recruitment of Act1 and TRAF6. IL-17RB, but not IL-17RA, contains an intracellular TRAF6-binding motif, which activates NF-kB, but not AP-1, through TRAF6 binding. IL-17B and IL-17C bind to IL-17RB and IL-17RE, respectively; however, the downstream signaling pathway is unknown.

The ligand(s) for IL-17RD is also unknown. FnIII, fibronectin III-like domain; SEFIR, similar expression to FGF, IL-17R, and Toll-IL-1R family domain.

Immunity 34, February 25, 2011ª2011 Elsevier Inc. 151

Immunity

Review

Fig. I-3. IL-17 and the IL-17receptor families.

Six IL-17 family cytokines (IL-17A to IL-17F) and five IL-17R family receptors (IL-17RA to IL-17RE) have been identified. After binding of an IL-17A or IL-17F homodimer or heterodimer to IL-17R (the heterodimer of IL-17RA and IL-17RC), Act1 associates with IL-17RA and/or IL-17RC through its SEFIR domains. Subsequently, the complex associates with TRAF6, leading to the activation of NF-κB, MAPK-AP-1, and C/EBP. Similar to signaling via IL-17R, IL-17E (IL-25) binding to IL-25R (heterodimer of IL-17RA and IL-17RB) results in activation of NF-κB, MAPK-AP-1, and C/EBP via recruitment of Act1 and TRAF6. IL-17RB, but not IL-17RA, contains an intracellular TRAF6-binding motif, which activates NF-κB. IL-17B and IL-17C bind to IL-17RB and IL-17RE, respectively;

however, the downstream signaling pathway is unknown. The ligand(s) for IL-17RD is also unknown.

FnIII, fibronectin III-like domain; SEFIR, similar expression to FGF, IL-17R, and Toll-IL-1R family domain.

Adapted from Immunity., 34: 149-162, 2011

It has been reported that chronic inflammation plays an important role in cancer development including angiogenesis, growth promotion, invasion, and metastasis of tumor cells (Lu et al., 2006). The infiltrating of IL-17A producing TH17 cells in tumor microenvironment contributes to generating a pro-inflammatory niche and promotes tumor progression in inflammation-associated gastric and pancreatic cancer, respectively (Iida et al., 2011; McAllister et al., 2014). IL-17A, which activates downstream signaling of STAT3 to up-regulate several pro-survival genes, also promotes invasion of breast cancer (Wang et al., 2009; Zhu et al., 2008). Compared to the promoting role of IL-17A in tumorigenesis, Furuta et al. found an opposite role of IL-17E in breast cancer tumorigenesis (Furuta et al., 2011). Secretion of IL-17E from non-malignant mammary epithelial cells induces caspase-mediated apoptosis in IL-17E receptor (also known as 25R, comprised of

IL-17RA/ IL-17RB

heterodimer) expressing breast cancer cells. IL-17RA and IL-17RB are also the receptors for IL-17A and IL-17B, respectively (Fig. I-4). Contradictory to the roles of IL-17E and its receptor in apoptosis, it is worth noting that overexpression of IL-17RB is observed in murine leukemia cells, suggesting an oncogenic role of this receptor (Tian et al., 2000). IL-17B, another cognate ligand of IL-17RB, may also play a role in promoting tumorigenesis (Fig. I-4). Thus, we hypothesize that the interaction of another cognate ligand IL-17B with IL-17RB may

results reveal the presence of two functionally distinct apoptotic reg-ulatory regions, a TRAF6-binding domain and a putative DD-like mo-tif, in the C terminus of IL-25R, demonstrating the intricacy of the signaling cascades involved in ligand-activated IL-25R function.

DISCUSSION

It is long appreciated that the prevalence of cancer in human pop-ulations is far lower than one would predict based on DNA mu-tation rates (23). If oncogenic mumu-tations are not sufficient to establish tumors, how are tumors contained, suppressed, or elimi-nated before they become evident? A number of tumor surveillance mechanisms have been described, including the classic molecular tumor suppressors, immune surveillance, and suppression by ECM and other microenvironmental factors. This study adds a new type of suppression to the list: factors secreted by normal dif-ferentiating cells that could kill or subdue their transformed coun-terparts.

We had shown previously that differentiating MECs secrete factors that allow phenotypic reversion of breast cancer cells, leading to for-mation of acinus-like structures and growth suppression (5). The se-creted factors could be partitioned into soluble and insoluble fractions;

the former had tumor cell–killing activity and the latter had most of the “reverting” activity. Here, we identified six factors in the soluble fraction that were secreted by differentiating MECs in 3D and shown to either kill or suppress the growth of tumor cells. This collection

of factors included antiangiogenic pro-teins (ATIII and VBP), proinflammatory cytokines (IL-1F7 and IL-25), and growth and differentiation proteins (FGF11 and BMP10). IL-25 exhibited the most potent cytotoxic activity toward breast cancer cells, whereas the other factors exhibited cytostat-ic activity. Here, we focused on the mech-anism of action of IL-25 and its potential as a therapeutic agent in breast cancer.

IL-25 is a proinflammatory cytokine that is expressed highly in certain organs, such as testis, prostate, and spleen, and is expressed in low amounts in other organs including normal breast (11, 24). It is the most distant member of the IL-17 family of proteins, sharing only 16 to 30% sequence homology with the other family members (25). It plays a role in proinflammatory responses of lymphatic, kidney, and lung cells by inducing production of T helper 2 (T

2)–type cytokines (11, 19, 24, 26).

The function of IL-25 in other tissues re-mains to be elucidated.

We show here that IL-25 is temporally up-regulated in developing normal mam-mary glands and induces caspase-mediated apoptosis of breast cancer cells without af-fecting nonmalignant MECs either in cul-ture or in mice. The reason behind the resistance of nonmalignant cells to IL-25 is the differential expression of the receptor, IL-25R, high in breast can-cer cells but low or absent in nonmalignant MECs (Fig. 5, A and B).

IL-25R overexpression contributes to tumorigenic potential, as shown by the result that siRNA-induced reduction in the amounts of IL-25R im-paired breast cancer cells’ anchorage-independent growth in soft agar (Fig. 5, C to E). Examination of breast cancer specimens showed dis-tinct up-regulation of IL-25R in 19% of the samples, correlating strongly in those with poor prognosis (Fig. 5I).

The exact mechanism by which IL-25R expression confers a growth advantage to breast cancer cells remains to be determined. We postu-late that although IL-25R–expressing cancer cells do not express the apoptotic ligand IL-25 (Fig. 2A and fig. S4A), they may express another ligand that contributes to their tumorigenic potential. Such a candidate ligand appears to be IL-17B, which binds IL-25R with a markedly lower affinity than that of IL-25 (11). We found that IL-17B was expressed in most breast cancer cell lines that expressed high amounts of IL-25R, whereas IL-17B was absent from nonmalignant MCF10A cells (fig. S4A).

Consistently, IL-17B was up-regulated in 30% of breast cancer speci-mens examined (12 of 40), but undetectable in normal tissues (0 of 18) (fig. S4B). Small hairpin RNA (shRNA)–dependent reduction of IL-17B amounts in MDA-MB468 breast cancer cells impaired their growth and invasive potentials (fig. S4, C to G), whereas ectopic addi-tion of IL-17B protein enhanced both potentials (fig. S4, H to J). These results in sum suggest that IL-17B may augment the tumorigenicity of breast cancer cells in an autocrine manner. This possibility is presently under investigation. Whether IL-17B competes directly with IL-25 for receptor binding is not known. However, it is known that both IL-25 Fig. 7. Death domain (DD)–like region of IL-25R renders cells sensitive to apoptotic signaling after

treat-ment with IL-25. (A) Schematics for IL-25R protein expressed in mutation analyses. Wt, wild-type full-length IL-25R protein; DTRAF6, mutated IL-25R with a deletion in TRAF6 binding domain (amino acids D339–341); DDD, mutated IL-25R with a deletion in the DD-like region (amino acids D376–387). (B) West-ern blot shows that increased IL-25R amounts (Wt, DTRAF6, or DDD) after IL-25R were ectopically expressed in MCF10A cells compared to the endogenous IL-25R amounts in parental cells (Ctrl). b-Actin served as an internal control. (C) DD-like domain of IL-25R is essential for apoptotic signaling mediated by IL-25. Western blot analysis was used to detect cleavage of caspase 3 and PARP in MCF10A cells that expressed IL-25R as in (B) after treatment with IL-25 (500 ng/ml, ~25 nM) for varying time periods. b-Actin served as an internal control. Black arrowheads, uncleaved protein; white arrowheads, cleaved protein. (D) Schematic for the cytotoxic activity of IL-25 specific to breast cancer cells that express IL-25R. Non-malignant MECs do not express IL-25R and are resistant to apoptosis induced by IL-25. Breast cancer cells that express IL-25R are susceptible to IL-25–induced apoptosis.

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on April 13, 2011 stm.sciencemag.org Downloaded from

Fig. I-4. Cytotoxic activity of IL-25 (IL-17E) is specific to IL-25R (IL-17RA/

IL-17RB heterodimer) expressing breast cancer cells. Non-malignant MECs do not express IL-25R and are resistant to apoptosis induced by IL-25.

Adapted from Sci Transl Med., 3: 78ra31, 2011

exert a different function rather than IL-17E induced apoptosis in breast carcinogenesis.

To test this possibility, my first study focuses on elucidating the role of IL-17RB/IL-17B signaling in breast cancer tumorigenesis.

Microenvironment of breast cancer cells

Growth of cancer cells is subjected to multiple signals regulation including autocrine/paracrine signals from cancer cells as well as various cell types in the local environment (also known as microenvironment). Accumulating evidence suggests that the microenvironment of tumor cell plays a vital role in cancer initiation and progression of many cancers (Liotta cancer progression, the numbers of fibroblasts and infiltrated immune cells are increased and the angiogenesis is also enhanced (Fig. I-5B).

The phenotypic change in microenvironment can be observed even in the early stage of breast cancer, ductal carcinoma in situ (DCIS). Allinen et al. isolated and examined the

serial analysis of gene expression (SAGE). In addition, genetic changes were detected by cDNA array compre-hensive genomic hybridization and single nucleotide poly morphism arrays. Th e results of this study

demon strated altered gene expression patterns in each cell type analyzed during breast cancer progression.

Myoepithelial cells from normal breast tissue and DCIS had the highest number of diﬀ erentially expressed genes.

Figure 1. Alterations of the microenvironment from normal duct to in situ transition. (A) Schematic (transverse) view of a normal breast duct composed of a layer of luminal epithelial cells encircled by myoepithelial cells (green) and surrounded by a continuous basement membrane.

Stroma containing fi broblasts, immune cells, and vasculature surrounded by the extracellular matrix maintains the normal tissue structure.

(B) Longitudinal view of the normal duct and in situ carcinoma. In ductal carcinoma in situ (DCIS), epigenetically and phenotypically altered myoepithelial cells (shown as brown cells) are surrounded by a still largely continuous basement membrane. Altered myoepithelial cells in DCIS are unable to aid polarization and organize the structure of the normal duct. At the same time in the stroma, the numbers of fi broblasts and infi ltrated leukocytes are increased and angiogenesis is enhanced. Cancer-associated fi broblasts (shown as yellow-green fi broblasts) and infi ltrated leukocytes elevate secretion of growth factors, cytokines, chemokines, and matrix metalloproteinases (MMPs) to promote tumor progression. Potential cross-talk between cell-cell and cell-matrix interactions are aberrantly regulated by both autocrine and paracrine networks of proteolytic enzymes, cytokines, and chemokines (red arrows; not all possible interactions are indicated). Interactions between stromal and cancer cells may interact with each other via paracrine signaling rather than direct cell-cell contact.

Myoepithelial cells Place et al. Breast Cancer Research 2011, 13:227

http://breast-cancer-research.com/content/13/6/227 Page 2 of 11

Fig. I-5. Alterations of the microenvironment from normal duct to in situ transition.

(A) Normal breast duct consists of a luminal epithelial layer encircled by

myoepithelial cells and surrounded by basement membrane. (B) Longitudinal view of the normal duct and in situ carcinoma. In ductal carcinoma in situ (DCIS), the numbers of fibroblasts and infiltrated immune cells are increased and the angiogenesis is also enhanced.

Adapted from Breast Cancer Res., 13: 227, 2011

global gene expression profiles of major cells types including fibroblasts, infiltrated immune cells, endothelial and luminal/myoepithelial cells from normal breast tissue, DCIS, and IDC (invasive ductal carcinoma) lesions (Allinen et al., 2004). The results demonstrated that gene expression profiles are altered in each cell types during breast cancer progression. A significant fraction of these altered genes encode secreted proteins and cell surface receptors, suggesting that the activation of aberrant autocrine/paracrine loops occurs. Deciphering of crosstalk between breast cancer and stromal cells in the microenvironment may lead to develop novel therapeutic strategies and targets.

Fibroblast and breast tumorigenesis

In most of cancer microenvironment studies, cancer-associated fibroblasts (CAFs) attract a lot of attention in the last decade. In the tumor stroma, connective tissue fibroblasts adjacent to cancer cells can be activated (or educated) as CAFs, which can be defined by expression of alpha smooth muscle actin (αSMA) (Paunescu et al., 2011).

Although the detailed mechanisms for the activation of CAFs remain uncertain, TGF-β and CXCL12/SDF-1 are regarded as the main factors that contribute to CAFs activation (Kojima et al., 2010). Compared to inactivated normal fibroblasts, activated CAFs play important roles in several tumor-promoting functions including sustaining proliferative signaling, inducing angiogenesis, activating invasion and metastasis (Hanahan and Coussens, 2012). In breast cancer, CAFs promote breast cancer progression and metastasis via several growth factors and chemokines secretion. For example, HGF and CXCL12/SDF-1 secreted from CAFs promote breast cancer cell growth through their receptors c-Met and CXCR4, respectively (Orimo et al., 2005; Rong et al., 1992; Tyan et al., 2011). The secretion of CXCL12/SDF-1 from CAFs also promotes angiogenesis via recruiting endothelial progenitor cells in breast cancer (Orimo et al., 2005). In sum, these

studies suggest that CAFs play an active role in breast tumorigenesis.

Adipocytes and breast cancer

Compared to the role of CAFs in breast cancer tumorigenesis, little attention has been given to the adipocytes despite the fact that adipocytes are the most abundant stromal partners in human mammary gland. Originally, adipocytes is regarded as energy storage cells, have clearly emerged as endocrine cells in the last decade. Adipocytes can secrete many factors such as hormones, growth factors, chemokines and pro-inflammatory molecules, also known as adipokines (Rajala and Scherer, 2003). Thus,

在文檔中細胞激素受體 IL-17RB 與乳腺脂肪細胞在乳癌癌化過程中所扮演之角色 (頁 9-20)