Skip Navigation


Carcinogenesis Advance Access originally published online on September 24, 2007
Carcinogenesis 2008 29(1):9-14; doi:10.1093/carcin/bgm215
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
29/1/9    most recent
bgm215v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (3)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Glick, A. B.
Right arrow Articles by Mohammed, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Glick, A. B.
Right arrow Articles by Mohammed, J.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Context-dependent regulation of cutaneous immunological responses by TGFβ1 and its role in skin carcinogenesis

Adam B. Glick1,*, Rolando Perez-Lorenzo1,2 and Javed Mohammed1

1 Department of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis, Life Sciences Building, The Pennsylvania State University, University Park, PA 16801, USA
2 Centro de Investigaciones en Enfermedades Tropicales, Universidad Autonoma de Campeche, Campeche, 24030, Mexico

* To whom correspondence should be addressed. Tel: +814 865 7170; Fax: +814 863 1696;Email: abg11{at}psu.edu


   Abstract
Top
 Abstract
Introduction
 Conclusions/future directions
 Funding
 References
 
Transforming growth factor β1 (TGFβ1) signaling plays a critical role in skin carcinogenesis. While most studies have focused on TGFβ1 signaling and response in keratinocytes, it is now becoming clear that the interaction of keratinocyte-derived TGFβ1 with cells of the immune system has an equally important role in tumor development. Tumors form within the context of innate and adaptive immune responses and studies in skin and skin carcinogenesis models have provided important insight into the impact of context-dependent pro-inflammatory and immunosuppressive actions of TGFβ1 on tumor development. Indeed, the paradigm of TGFβ1 duality is clearly evident in its ability to both promote and inhibit inflammatory responses. Recent studies have begun to shed new light on the molecular basis for these actions and to provide insight into how these may contribute to context-dependent effects of TGFβ1 on carcinogenesis in the skin and other epithelial tissues.

Abbreviations: DC, dendritic cell; DMBA, 7-12-dimethylbenz[a]anthracene; IL, interleukin; LC, Langerhans cells; NK, natural killer; SCC, squamous cell carcinoma; TGFβ1, transforming growth factor β1; Th, T helper cell; TNF{alpha}, tumor necrosis factor-{alpha}; TPA, 12-O-tetradecanoylphorbol-13-acetate; Treg, regulatory T cell


   Introduction
Top
 Abstract
 Introduction
Conclusions/future directions
 Funding
 References
 
The regulation of the immune system by transforming growth factor β1 (TGFβ1) is very important in the development of epithelial cancers. TGFβ1 is made and responded to by keratinocytes and fibroblasts in the skin as well as resident and infiltrating cells of the immune system. It is initially secreted as a biologically latent complex that requires extracellular activation for receptor binding to occur and subsequent induction of gene expression through the transcription factors Smad2 or Smad3 complexed with Smad4 (1). Nearly all studies show that inhibition of TGFβ1 signaling in genetically altered keratinocytes accelerates chemically or ras oncogene-induced squamous cell carcinoma (SCC) formation (2), and that chemically induced papillomas with a high frequency of malignant conversion do not have detectable TGFβ1 protein within the epithelial or stromal component of the tumor (3,4) even though TGFβ1 messenger RNA is elevated in both papillomas and SCC (4–6). However, highlighting the striking context-dependent effects of TGFβ1 on epithelial carcinogenesis, over-expression of TGFβ1 in papillomas can accelerate invasion and metastasis (7). This context dependence is also critical when examining the relationship between TGFβ1 expression, the immune system and skin tumor development. This review examines the role of TGFβ1 regulation of the immune system and the relevance of this for cancer development within the context of cutaneous SCC and the multistage skin carcinogenesis model.

TGFβ1 and acute cutaneous inflammation
Inflammation in the skin represents an immune response that provides vital protection from exposure to environmental pathogens, ultraviolet radiation and trauma. The ability of TGFβ1 to both stimulate and inhibit activities of different immune cells is critical in the regulation of the normal inflammatory response. In general, the primary inflammatory response to diverse stimuli is the production of interleukin (IL)-1{alpha}, tumor necrosis factor-{alpha} (TNF{alpha}) and other primary pro-inflammatory cytokines by keratinocytes (8). These in turn activates a pro-inflammatory phenotype in dermal fibroblasts, endothelial cells, resident leukocytes as well as keratinocytes (9,10) and rapid infiltration of innate immune cells including neutrophils, monocytes and mast cells.

The pro-inflammatory actions of TGFβ1 were first observed following subcutaneous injection of TGFβ1 into mouse skin where it induced granulation tissue and rapid accumulation of leukocytes at the injection site (11). Subsequent studies showed that TGFβ1 induces differentiation of monocytes to dendritic cells (DCs) (12), chemotaxis of CD4+ and CD8+ T cells, neutrophils and monocytes/macrophages and mast cells (13–15) and stimulates expression of FC{gamma}RIII receptor and release of cytokines from immature and newly recruited monocytes (14,16,17), all of which are important in amplifying the inflammatory process (Figure 1). Following wounding of Smad3–/– mice there is reduced monocyte infiltration into the wound site and reduced monocyte chemotaxis toward TGFβ1 in vitro (18). Similarly, in the absence of Smad3, the dermal influx of mast cells, macrophages and neutrophils and fibrosis caused by gamma irradiation is significantly reduced (19). Thus, integrity of the Smad3 pathway is essential for the inflammatory response to trauma.


Figure 1
View larger version (34K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1. Dual effects of TGFβ1 on cells of the innate immune system. TGFβ1 promotes chemotaxis of neutrophils, mast cells and monocytes. It stimulates expression of FC{gamma}RIII receptor and production of cytokines by newly recruited monocytes, thereby producing an inflammatory response that can be amplified during tumor promotion. TGFβ1 is also required for epidermal migration and differentiation of LCs. Apart from promoting an inflammatory milieu, TGFβ1 can reduce cytotoxic ability of NK cells by down-regulating activating receptors, NKG2D and NKp30, and supressing interferon{gamma} production. TGFβ1 inhibits toll-like receptor and non-toll-like receptor-mediated neutrophil degranulation and production of nitric oxide and superoxide by mast cells. Elevated TGFβ1 in skin tumors also leads to inhibition of LC migration from skin to draining lymph nodes. These effects of TGFβ1 lead to a decrease in innate immune response and reduced immunosurveillance during skin carcinogenesis.

 
A second component of the inflammatory response is cutaneous infiltration of antigen-specific cells of the adaptive immune system. This is stimulated by migration of antigen-activated Langerhans cells (LCs) and dermal DCs, the cutaneous antigen-presenting cells, to the skin draining lymph nodes and presentation of these antigens to naive and central memory T cells (20). LCs require TGFβ1 for maturation and migration to the epidermis as they are absent in the epidermis of the Tgfβ1–/– mouse (21,22), but can be expanded from Tgfβ1–/– bone marrow and are present in normal numbers in transgenic mice with keratinocyte-specific TGFβ1-signaling defects (21,22). More recent studies have shown that TGFβ1 induces DC differentiation from CD34+ progenitor cells in vitro and can induce genes associated with LC migration (23). Although it is not known how changes in epidermal TGFβ1 expression could alter LC responses to inflammatory stimuli, several studies (see below) suggest that tumor cell production of TGFβ1 could alter the LC response to tumor antigens.

Following their activation by LC or macrophages, T cells proliferate and differentiate into memory/effector T cells and migrate to the skin. Dependent on the specific cytokine environment and inflammatory stimuli, activated T cells release further cytokine sets that promote either a T helper cell (Th)1- or Th2-type adaptive immune response (24). Once the infection is cleared or wound is healed, the inflammatory response must be suppressed and this can occur through reduced production of pro-inflammatory cytokines and through expression of immunosuppressive cytokines (25). TGFβ1 is crucial in this final stage of the inflammatory processes. The pronounced multiorgan inflammatory disease in the Tgfβ1–/– mouse (26) highlights the critical importance of TGFβ1 in suppressing inflammation through its inhibitory effects on both innate and adaptive immune cell function (27). TGFβ1 alters the differentiation of CD4+ cells (28,29) by inhibiting Th1 responses through suppression of interferon{gamma} production by natural killer (NK) cells (30) and blocks the maturation and activation of DC by reducing their ability to present antigen and to stimulate T-cell proliferation (31). Tgfβ1 can suppress IL-2 production and CD8+ cytotoxic T lymphocytes activation (32). TGFβ1 also inhibits toll-like receptor and non-toll-like receptor ligand-mediated neutrophil degranulation with no apparent effect in the chemotactic response to IL-8 (33) and inhibits activated mast cells through the down-regulation of both the expression of pro-inflammatory cytokines and the production of nitric oxide and superoxide ion (34). Again the duality of responses is apparent when inflammatory responses in genetically altered mice are measured. Thus, in a mouse model of cutaneous dermatitis induced by epicutaneous application of ovalbumin, the absence of Smad3 results in suppression of ovalbumin-induced increase in dermal thickness and expression of pro-inflammatory cytokines IL-6 and IL-1β. In contrast, loss of Smad3 increases the number of infiltrating mast cells and causes elevated levels of ovalbumin-specific IgE (35).

TGFβ1, chronic inflammation and cutaneous cancer
While the normal inflammatory process is tightly regulated and self-limiting, chronic inflammation is a pathological condition marked by constant influx of cells of the adaptive and innate immune system, production of pro-inflammatory cytokines and tissue remodeling. These pathological tissue changes provide an environment conducive to tumor development (36). There is clinical evidence linking chronic inflammation with cutaneous SCC developing in non-healing wounds in leg ulcerations, lupus erythematosus, osteomyelitis, perineal inflammatory disease, ulcerative lichen planus, epidermolysis bullosa (37–43) and chronic wounds secondary to burns or trauma (44,45). In many of these chronic inflammatory diseases and conditions, TGFβ1 signaling is blocked or expression is down-regulated in one or more cell types such that its anti-inflammatory properties are reduced (46–49). Although psoriasis carries no increased risk for SCC formation (50), there is again diminished local expression of TGFβ1 and TGFβ1 receptor but elevated plasma TGFβ1 levels (51–53). Reduced TGFβ1 signaling is similar to other chronic inflammatory states such as inflammatory bowel disease. Here, TGFβ1 signaling is blocked in both gut epithelium and T cells due to elevated expression of Smad7, which blocks Smad-dependent TGFβ1 signal transduction such as Tgfβ1-mediated suppression of pro-inflammatory cytokine expression (54). However, when characteristic inflammation of the Tgfβ1–/– mouse is blocked by breeding onto a Rag 2–/– background and the mice are kept in a helicobacter-free environment, inflammation and cancer development in the gut is blocked (55). Similar results occur with Smad3-null mice (56). Thus, cancer development is provoked by reduced TGFβ1 signaling within an inflammatory environment. Indeed, over-expression of Smad7 in the epidermis blocks pro-inflammatory signals linked to activation of nuclear factor kappa B. This occurs through the interaction of Smad7 with adaptor proteins TAB2 and TAB3 which link the TGFβ1 activated kinase with pro-inflammatory signals. Interaction of Smad7 with these molecules suppresses TNF{alpha}-induced nuclear factor kappa B (NF-{kappa}B) activation and inflammation (57).

Skin carcinogenesis models have also provided experimental evidence for a role of inflammation in cancer development. In the two-stage chemical carcinogenesis model, the mouse epidermis is treated once with the carcinogen 7, 12-dimethyl benz[a]-anthracene (DMBA) followed by 20 weekly applications of a tumor promoter, such as the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), a potent activator of protein kinase C. Benign papillomas with initiating mutations in the c-Ha ras gene arise within 10–15 weeks, and a small percentage progress to locally invasive SCC with additional genetic changes (58). Development of papillomas occurs within the context of a strong inflammatory infiltrate caused by the tumor promoter TPA. TPA activation of protein kinase C and downstream targets AP-1 and nuclear factor kappa B stimulates the expression of a wide variety of pro-inflammatory cytokines (59) such as TNF{alpha}, MIP-1{alpha} and MIP-2 and causes rapid influx of neutrophils and other innate immune cells into skin. Many of the same physiological changes induced by TPA occur during wound healing, and indeed wounding can replace TPA as a tumor-promoting stimulus (60,61). Interestingly in the Rous sarcoma virus fibrosarcoma tumor model in chickens, injection of TGFβ1 can replace wounding as a tumor-promoting stimulus (62), although this has not yet been demonstrated for epidermal tumors in mice. Tumor promotion appears to be tightly linked to this inflammatory reaction as non-promoting phorbol esters do not induce inflammation. Transgenic mice expressing pro-inflammatory genes in the skin have reduced requirement for tumor promotion and treatment with anti-inflammatory agents inhibits tumor formation (63–67). However, this relationship is likely to be more complex since mice over-expressing the pro-inflammatory mediator IL-1{alpha} in the skin are completely resistant to tumor induction by the two-stage carcinogenesis protocol (68). Nevertheless, an epidermally targeted Human Papilloma Virus E6/E7 transgenic mouse model also supports the concept that inflammation is a tumor promoter. In this model, the skin progresses through a hyperplastic and dysplastic state to SCC that is dependent on B cell-driven infiltration of mast cells (69,70).

TGFβ1 expression is rapidly and transiently induced in the suprabasal compartment following treatment of mouse skin with TPA and other tumor promoters (6,71) and although the exact role in promotion is not clear, the inhibition of TPA-induced hyperplasia by a skin-targeted TGFβ1 transgene (72) and exaggerated inflammatory response to TPA in Tgfβ1–/– skin grafts (73) indicates that TGFβ1 probably acts as a negative feedback for TPA-induced hyperproliferation and inflammation. However, the acute inflammatory response to TPA is not altered in Smad3–/– mice, although these mice are resistant to TPA-induced promotion of skin tumors due to a blocked keratinocyte proliferative response (74). Thus, Smad3 has distinct roles in the inflammatory response dependent on the nature of the inflammatory stimulus.

Given that TGFβ1 can both activate and inhibit an inflammation, it is of considerable interest that several transgenic mouse models over-expressing either active or latent TGFβ1 in the basal layer of the skin exhibit an inflammatory infiltrate coupled with angiogenesis (75,76). Lesions that develop in these mice express pro-inflammatory cytokines and chemokines similar to Th1 inflammatory diseases such as psoriasis (75). Expression of active TGFβ1 in the oral mucosa also caused a similar inflammatory and angiogenic response (77). Thus in the absence of an inflammatory signal to inhibit, TGFβ1 over-expression appears to provoke a chronic inflammatory response, although is not yet clear if the inflammatory infiltrate occurring under these conditions is similar to that following TPA treatment or wounding. Interestingly, in all of these over-expression models the epidermis becomes hyperproliferative even though responses to acute proliferative stimuli can be blocked by the initial over-expression of TGFβ1. Either keratinocytes become unresponsive to TGFβ1 with time due to down-regulation of TGFβ1-signaling components or secondary factors produced by the inflammatory cells stimulate keratinocyte proliferation. Under these conditions, chronic inflammation caused by TGFβ1 may act as a tumor-promoting stimulus, although this has not yet been demonstrated (Figure 1).

Is this pro-inflammatory effect of TGFβ1 direct or indirect? Recent studies linking TGFβ1 to the generation of Th17 lineage T cells provides a potential mechanism for the chronic inflammatory state under conditions of TGFβ1 over-expression in the skin. TGFβ1 producing CD4+CD25+ or TGFβ1 itself with IL-6 can induce naive T cells to a Th17 phenotype which is characterized by secretion of the pro-inflammatory cytokines IL-17A and IL-17F (Figure 2). These cytokines induce rapid recruitment of polymorphonuclear leukocytes to sites of acute infections or wounds (78,79). A positive regulatory loop caused by further release of pro-inflammatory cytokines such as IL-1β, IL-6 and TNF{alpha} may act to sustain the Th17 cell and the inflammatory state. Interestingly, Th17 cells do not express Smad7 (78), thus it is possible that the inflammatory milieu elevates Smad7 in all infiltrating leukocytes except the Th17 cells, making them resistant to immunosuppressive effects of TGFβ1 over-expression.


Figure 2
View larger version (27K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 2. A model for the regulation of T-cell phenotype by TGFβ1 and its effects on cancer development. The balance between Th17 and Treg cells within a tumor may contribute to the inhibitory or promoting effects of TGFβ1. TGFβ1 over-expression by normal keratinocytes can induce a Th17 phenotype with production of IL-17 and establishment of chronic inflammation. This leads to up-regulation of pro-inflammatory cytokines, infiltration of innate immune cells and a reactive stromal environment. Whether chronic inflammation in the context of TGFβ1 over-expression creates a tumor-promoting or inhibitory environment is unclear. Over-expression of TGFβ1 by tumor cells that may themselves be resistant to this cytokine can induce a Treg cell phenotype (CD4+CD25+FoxP3+) which inhibits cytotoxic T-cell activity and supresses immunosurveillance. Treg cells in presence of TGFβ1 and IL-6 also promote the development of Th17 cells but the impact of this for tumor progression is not yet known.

 
Immunosurveillance and cutaneous cancer
While chronic inflammation is clearly linked to the development of cutaneous cancer there is also clear evidence for tumor-suppressive immunosurveillance mechanisms. Immunosuppression caused by organ transplantation (80,81) or due to ultraviolet irradiation is linked to increased risk for development of squamous cancer (82). Conversely, activation of the immune system using topical treatment with the immunomodulator imiquimod [1-(2-methylpropyl)-1H-imidazo [4,5-C]quinolin-4-amine] can cause regression of cutaneous cancers (83–85). In this case, an acute localized inflammatory response caused by release of pro-inflammatory cytokines such as interferon{alpha}, TNF{alpha}, IL-12 and IL-1{alpha} leads to tumor cell degeneration and complete clinical response within several weeks of therapy (86). Spontaneous regression of keratoacanthoma, a well-differentiated form of SCC is associated with increased CD4+ T-cell infiltration compared with invasive SCC (87,88), and the histological and immunological profile of imiquimod-treated lesions is very similar to these regressing tumors (86). These studies highlight the need to define the nature of the inflammatory infiltrate as a tumor-promoting or antitumor response.

In mice, deletion of key immunoregulatory genes such as Ifn {gamma} or Prf1 leads to enhanced skin tumor formation (89–91). Similarly, mice with deletion of the T-cell receptor {delta} locus and thereby lacking skin resident {gamma}{delta} T cells have increased frequency of chemically induced papillomas and increased frequency of malignant conversion, suggesting that this T-cell population is important in antitumor immunosurveillance (92,93).

In the two-stage skin carcinogenesis protocol, the benign papillomas that form after TPA promotion differ in their risk for malignant progression. The majority undergo limited progression and do not convert to SCC, while a smaller number termed high-risk papillomas are the likely precursors to SCC (58). Although acute and chronic TPA treatment produces a pronounced inflammatory response and outgrowth of papillomas is dependent on this inflammatory response, recent microarray analysis of early low- and high-risk papillomas indicates that high-risk papillomas and SCC have reduced expression of pro-inflammatory genes and reduced levels of CD3+ T cells relative to the majority of papillomas that do not convert to SCC (94). Thus, in this model while inflammation is important for outgrowth of benign tumors, localized reduced immunosurveillance is associated with benign tumors that undergo conversion to SCC.

TGFβ1 and tumor immunosurveillance
Some of the immunosuppressive actions of TGFβ1 that function to resolve inflammation may play a crucial role in allowing malignant cells to escape from immunosurveillance. T cells are a major target of TGFβ1 produced by tumor cells, as tumor cells transfected with a TGFβ1 cDNA suppressed cytotoxic T lymphocytes function both in vitro and in vivo and escaped immunosurveillance (95) and highly metastatic tumor cell lines that naturally produce TGFβ1 were incapable of growing in transgenic mice in which both CD8+ and CD4+ T cells were unable to respond to TGFβ1 due to expression of a dominant-negative TGFβ type II receptor transgene (96). Interestingly, reconstitution studies showed that inhibition of tumor growth was directly linked to development of tumor-specific cytotoxic T lymphocytes activity by the TGFβ1-insensitive CD8+ cells (96). TGFβ1 can induce a regulatory T cell (Treg) phenotype in naive T cells through up-regulation of the transcription factor FoxP3. These CD4+CD25+FoxP3+ T cells can suppress effector function of CD4+ and CD8+ T cells and DCs (97,98), possibly through TGFβ1 production although this is controversial (99,100). In contrast to CD4+CD25+FoxP3+ Treg cells which use cell surface TGFβ1 and cell–cell contact to regulate other immune cells, inducible Treg cells (Th3) that occur in the periphery can exert their regulatory functions through secreted TGFβ1 (25). In vivo Treg cells have no effect on infiltration or expansion of tumor-specific CD8+ T cells but specifically block their cytotoxic function through a TGFβ1-dependent mechanism (101). Tumor cells expressing high levels of TGFβ1 can directly convert CD4+CD25–FoxP3– T cells to Treg cells (102). However, it is not known if this occurs during the in vivo development of a tumor and is responsible for tumor progression. Interestingly, CD4+CD25+FoxP3+ cells can induce Th17 differentiation of CD4+CD25– T cells and if activated in the presence of IL-6 but the absence of exogenous TGFβ1 can themselves differentiate into Th17 cells (103). Thus, the effect of TGFβ1 on inflammation and immunosuppression may be dependent on the balance between Treg and Th17 induction (Figure 2).

While TGFβ1 regulation of T-cell phenotype has not yet been implicated directly in skin tumor progression, its effects on LC, the epidermal antigen-presenting cells, appear to be critical. Elevated TGFβ1 expression in human and murine skin tumor xenografts that progress instead of regress when transplanted is due to inhibition of LC migration from the skin to the local lymph node and suppression of maturation into potent T-cell activators (104). SCC regressor lines can be converted to ones that grow in syngeneic hosts by over-expression of TGFβ1 (105). Again DC migration from the tumor to the regional lymph node and CD4+ and CD8+ T-cell infiltration into the tumor was blocked. Conversely, in a glioma xenotransplantation model tumor growth and invasiveness was reduced using a small molecule Activin-like kinase 5 inhibitor, but this was in large part due to increased infiltration of the tumor by CD8+ T cells, NK cells and macrophages rather than direct effects on tumor cell proliferation or apoptosis (106). These data suggest great potential in modulating antitumor immune responses via interference with the TGFβ1-signaling pathway.

The NKG2D receptors present on NK cells are an additional target for TGFβ1-mediated inhibition of antitumor immunosurveillance. Mice that lack NKG2D have an increased sensitivity to chemically induced tumors (107). TGFβ1 inhibits NK-mediated antitumor cytotoxicity through down-regulation of NKp30 and NKG2D receptors on NK cells which are responsible for the NK-mediated recognition and killing of fibrosarcomas (108–110).


   Conclusions/future directions
Top
 Abstract
 Introduction
 Conclusions/future directions
Funding
 References
 
The last decade of research in skin carcinogenesis has shown convincingly that autocrine TGFβ1 signaling in keratinocytes plays a critical role in inhibiting tumor development but that autocrine and paracrine TGFβ1 produced by keratinocytes can also accelerate invasion and metastasis. Most studies documenting these results have used mice with keratinocyte-specific over-expression or ablation of signaling, or whole animal knockouts of specific elements of this pathway. Although it is clear that TGFβ1 has context-dependent tumor-promoting and tumor suppressing actions on skin carcinogenesis as well as pro-inflammatory and immunosuppressive effects on cells of the cutaneous immune system, it is not completely clear how and under what circumstances they are linked mechanistically. To more clearly define how TGFβ1 effects on the cutaneous immune system regulates skin carcinogenesis, mouse models utilizing stage-specific modulation of TGFβ1 signaling and response in skin directed components of the immune system are needed. More studies are needed to determine factors that drive cutaneous inflammation occurring under conditions of TGFβ1 over-expression and whether this sustains or blocks tumor growth. Similarly, it is not clear if TGFβ1 over-expression within the context of a benign or malignant tumor would have the same effects on the immune system as over-expression in a normal epidermis. The relationship between absence of TGFβ1 production, reduced adaptive immunity and the high-risk benign tumor phenotype also should be explored further. Given the central role of TGFβ1 in regulating inflammatory and immunosurveillance pathways, there is great promise but also potential problems targeting this pathway for cancer therapy. Further studies on the context-dependent effects of TGFβ1 on both epithelial and immune cells during tumor progression should provide important information to guide future therapeutic studies.


   Funding
Top
 Abstract
 Introduction
 Conclusions/future directions
 Funding
References
 
A.G., R.P.-L. and J.M. were supported by CA117957 [GenBank] from the National Cancer Institute, National Institutes of Health.


   Acknowledgments
 
Conflict of Interest Statement: None declared.


   References
Top
 Abstract
 Introduction
 Conclusions/future directions
 Funding
 References
 

  1. Wakefield LM, et al. TGF-beta signaling: positive and negative effects on tumorigenesis. Curr. Opin. Genet. Dev. (2002) 12:22–29.[CrossRef][Web of Science][Medline]
  2. Glick AB. TGFbeta1. Back to the future. Revisiting its role as a transforming growth factor. Cancer Biol. Ther. (2004) 3:276–283.[Web of Science][Medline]
  3. Glick AB, et al. Loss of expression of transforming growth factor β in skin and skin tumors is associated with hyperproliferation and a high risk for malignant conversion. Proc. Natl Acad. Sci. USA (1993) 90:6076–6080.[Abstract/Free Full Text]
  4. Cui W, et al. Lack of transforming growth factor-β1 expression in benign skin tumors of p53null mice is prognostic for a high risk of malignant conversion. Cancer Res. (1994) 54:5831–5836.[Abstract/Free Full Text]
  5. Fowlis DJ, et al. Discordant transforming growth factor β1 RNA and protein localization during chemical carcinogenesis of the skin. Cell Growth Differ. (1992) 3:81–91.[Abstract]
  6. Patamalai B, et al. Altered expression of transforming growth factor-beta 1 mRNA and protein in mouse skin carcinogenesis. Mol. Carcinog. (1994) 9:220–229.[Web of Science][Medline]
  7. Weeks BH, et al. Inducible expression of transforming growth factor beta1 in papillomas causes rapid metastasis. Cancer Res. (2001) 61:7435–7443.[Abstract/Free Full Text]
  8. Kupper TS, et al. Immune surveillance in the skin: mechanisms and clinical consequences. Nat. Rev. Immunol. (2004) 4:211–222.[CrossRef][Web of Science][Medline]
  9. Murphy JE, et al. Interleukin-1 and cutaneous inflammation: a crucial link between innate and acquired immunity. J. Invest. Dermatol. (2000) 114:602–608.[CrossRef][Web of Science][Medline]
  10. Fuhlbrigge RC, et al. Adhesion molecules in cutaneous immunity. Semin. Immunopathol. (2007) 29:45–57.
  11. Roberts AB, et al. Transforming growth factor type beta: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc. Natl Acad. Sci. USA (1986) 83:4167–4171.[Abstract/Free Full Text]
  12. Randolph GJ, et al. The CD16(+) (FcgammaRIII(+)) subset of human monocytes preferentially becomes migratory dendritic cells in a model tissue setting. J. Exp. Med. (2002) 196:517–527.[Abstract/Free Full Text]
  13. Adams DH, et al. Transforming growth factor-beta induces human T lymphocyte migration in vitro. J. Immunol. (1991) 147:609–612.[Abstract]
  14. Wahl SM, et al. Transforming growth factor type beta induces monocyte chemotaxis and growth factor production. Proc. Natl Acad. Sci. USA (1987) 84:5788–5792.[Abstract/Free Full Text]
  15. Fan K, et al. Transforming growth factor-beta 1 bifunctionally regulates murine macrophage proliferation. Blood (1992) 79:1679–1685.[Abstract/Free Full Text]
  16. Welch GR, et al. Selective induction of Fc gamma RIII on human monocytes by transforming growth factor-beta. J. Immunol. (1990) 144:3444–3448.[Abstract]
  17. Cartney-Francis N, et al. TGF-beta regulates production of growth factors and TGF-beta by human peripheral blood monocytes. Growth Factors (1990) 4:27–35.[Medline]
  18. Ashcroft GS, et al. Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response [see comments]. Nat. Cell Biol. (1999) 1:260–266.[CrossRef][Web of Science][Medline]
  19. Flanders KC, et al. Mice lacking Smad3 are protected against cutaneous injury induced by ionizing radiation. Am. J. Pathol. (2002) 160:1057–1068.[Abstract/Free Full Text]
  20. Clark R, et al. Old meets new: the interaction between innate and adaptive immunity. J. Invest. Dermatol. (2005) 125:629–637.[CrossRef][Web of Science][Medline]
  21. Borkowski TA, et al. A role for endogenous transforming growth factor beta 1 in Langerhans cell biology: the skin of transforming growth factor beta 1 null mice is devoid of epidermal Langerhans cells. J. Exp. Med. (1996) 184:2417–2422.[Abstract/Free Full Text]
  22. Borkowski TA, et al. A role for TGFbeta1 in Langerhans cell biology. Further characterization of the epidermal Langerhans cell defect in TGFbeta1 null mice. J. Clin. Invest. (1997) 100:575–581.[Web of Science][Medline]
  23. Ju XS, et al. Transforming growth factor beta1 up-regulates interferon regulatory factor 8 during dendritic cell development. Eur. J. Immunol. (2007) 37:1174–1183.[CrossRef][Web of Science][Medline]
  24. Rankin JA. Biological mediators of acute inflammation. AACN Clin. Issues (2004) 15:3–17.[Medline]
  25. Mills KH. Regulatory T cells: friend or foe in immunity to infection? Nat. Rev. Immunol. (2004) 4:841–855.[CrossRef][Web of Science][Medline]
  26. Kulkarni AB, et al. Transforming growth factor-β1 null mutation in mice causes excessive inflammatory response and early death. Proc. Natl Acad. Sci. USA (1992) 90:770–774.[CrossRef][Web of Science]
  27. Letterio JJ, et al. Regulation of immune responses by TGF-beta. Annu. Rev. Immunol. (1998) 16:137–161.[CrossRef][Web of Science][Medline]
  28. Gorelik L, et al. Cutting edge: TGF-beta inhibits Th type 2 development through inhibition of GATA-3 expression. J. Immunol. (2000) 165:4773–4777.[Abstract/Free Full Text]
  29. Gorelik L, et al. Mechanism of transforming growth factor beta-induced inhibition of T helper type 1 differentiation. J. Exp. Med. (2002) 195:1499–1505.[Abstract/Free Full Text]
  30. Laouar Y, et al. Transforming growth factor-beta controls T helper type 1 cell development through regulation of natural killer cell interferon-gamma. Nat. Immunol. (2005) 6:600–607.[CrossRef][Web of Science][Medline]
  31. Strobl H, et al. TGF-beta1 regulation of dendritic cells. Microbes Infect. (1999) 1:1283–1290.[CrossRef][Web of Science][Medline]
  32. Herrmann S, et al. Both IL-2 and IL-4 synergize with IL-12 to induce a CTL response, a response completely blocked by TGF-beta. Ann. N. Y. Acad. Sci. (1996) 795:168–180.[CrossRef][Medline]
  33. Shen L, et al. Inhibition of human neutrophil degranulation by transforming growth factor-beta1. Clin. Exp. Immunol. (2007) 149:155–161.[Web of Science][Medline]
  34. Kashyap M, et al. TGF-beta1 inhibits late-stage mast cell maturation. Exp. Hematol. (2005) 33:1281–1291.[CrossRef][Web of Science][Medline]
  35. Anthoni M, et al. Smad3 signal transducer regulates skin inflammation and specific IgE response in Murine model of atopic dermatitis. J. Invest. Dermatol (2007) 127:1923–1929.[CrossRef][Web of Science][Medline]
  36. Coussens LM, et al. Inflammation and cancer. Nature (2002) 420:860–867.[CrossRef][Medline]
  37. Kaplan RP. Cancer complicating chronic ulcerative and scarifying mucocutaneous disorders. Adv. Dermatol. (1987) 2:19–46.[Medline]
  38. Mayron R, et al. Verrucous carcinoma arising in ulcerative lichen planus of the soles. J. Dermatol. Surg. Oncol. (1988) 14:547–551.[Web of Science][Medline]
  39. Gur E, et al. Squamous cell carcinoma in perineal inflammatory disease. Ann. Plast. Surg. (1997) 38:653–657.[Web of Science][Medline]
  40. Sarani B, et al. Squamous cell carcinoma arising in an unhealed wound in Crohn's disease. South Med. J. (1997) 90:940–942.[Web of Science][Medline]
  41. Mallipeddi R, et al. Increased risk of squamous cell carcinoma in junctional epidermolysis bullosa. J. Eur. Acad. Dermatol. Venereol. (2004) 18:521–526.[CrossRef][Web of Science][Medline]
  42. Yamada T, et al. Squamous cell carcinoma arising on scars of epidermolysis bullosa acquisita. Br. J. Dermatol. (2005) 152:588–590.[CrossRef][Web of Science][Medline]
  43. Kowal-Vern A, et al. Burn scar neoplasms: a literature review and statistical analysis. Burns (2005) 31:403–413.[CrossRef][Web of Science][Medline]
  44. Esther RJ, et al. Marjolin ulcers: secondary carcinomas in chronic wounds. J. South. Orthop. Assoc. (1999) 8:181–187.[Medline]
  45. Trent JT, et al. Wounds and malignancy. Adv. Skin Wound Care (2003) 16:31–34.[CrossRef][Medline]
  46. Jackson M, et al. Activation of transforming growth factor-beta1 and early atherosclerosis in systemic lupus erythematosus. Arthritis Res. Ther. (2006) 8:R81.[CrossRef][Medline]
  47. Kim BC, et al. Fibroblasts from chronic wounds show altered TGF-beta-signaling and decreased TGF-beta type II receptor expression. J. Cell. Physiol. (2003) 195:331–336.[CrossRef][Web of Science][Medline]
  48. Hammad AM, et al. Transforming growth factor beta 1 in children with systemic lupus erythematosus: a possible relation with clinical presentation of lupus nephritis. Lupus (2006) 15:608–612.[Abstract/Free Full Text]
  49. Karatsaidis A, et al. Inhibition of the transforming growth factor-beta/Smad signaling pathway in the epithelium of oral lichen. J. Invest. Dermatol. (2003) 121:1283–1290.[CrossRef][Web of Science][Medline]
  50. Nickoloff BJ, et al. Inflammation and cancer: is the link as simple as we think? J. Invest. Dermatol. (2005) 124:x–xiv.[CrossRef][Web of Science][Medline]
  51. Flisiak I, et al. Association between psoriasis severity and transforming growth factor beta(1) and beta (2) in plasma and scales from psoriatic lesions. Cytokine (2002) 19:121–125.[CrossRef][Web of Science][Medline]
  52. Doi H, et al. Downregulation of TGFbeta isoforms and their receptors contributes to keratinocyte hyperproliferation in psoriasis vulgaris. J. Dermatol. Sci. (2003) 33:7–16.[CrossRef][Web of Science][Medline]
  53. Flisiak I, et al. Plasma transforming growth factor beta1 as a biomarker of psoriasis activity and treatment efficacy. Biomarkers (2003) 8:437–443.[CrossRef][Web of Science][Medline]
  54. Monteleone G, et al. Blocking Smad7 restores TGF-beta1 signaling in chronic inflammatory bowel disease. J. Clin. Invest. (2001) 108:601–609.[CrossRef][Web of Science][Medline]
  55. Engle SJ, et al. Elimination of colon cancer in germ-free transforming growth factor beta 1-deficient mice. Cancer Res. (2002) 62:6362–6366.[Abstract/Free Full Text]
  56. Maggio-Price L, et al. Helicobacter infection is required for inflammation and colon cancer in SMAD3-deficient mice. Cancer Res. (2006) 66:828–838.[Abstract/Free Full Text]
  57. Hong S, et al. Smad7 binds to the adaptors TAB2 and TAB3 to block recruitment of the kinase TAK1 to the adaptor TRAF2. Nat. Immunol. (2007) 8:504–513.[CrossRef][Web of Science][Medline]
  58. Glick A, et al. The high-risk benign tumor: evidence from the two-stage skin cancer model and relevance for human cancer. Mol. Carcinog. (2007) 46:605–610.[CrossRef][Web of Science][Medline]
  59. Cataisson C, et al. Activation of cutaneous protein kinase C alpha induces keratinocyte apoptosis and intraepidermal inflammation by independent signaling pathways. J. Immunol. (2003) 171:2703–2713.[Abstract/Free Full Text]
  60. Martins-Green M, et al. Inflammation is responsible for the development of wound-induced tumors in chickens infected with Rous sarcoma virus. Cancer Res. (1994) 54:4334–4341.[Abstract/Free Full Text]
  61. Argyris TS. Tumor promotion by abrasion induced epidermal hyperplasia in the skin of mice. J. Invest. Dermatol. (1980) 75:360–362.[CrossRef][Web of Science][Medline]
  62. Sieweke MH, et al. Mediation of wound-related Rous sarcoma virus tumorigenesis by TGF-beta. Science (1990) 248:1656–1660.[Abstract/Free Full Text]
  63. Fischer SM, et al. Chemopreventive activity of celecoxib, a specific cyclooxygenase-2 inhibitor, and indomethacin against ultraviolet light-induced skin carcinogenesis. Mol. Carcinog. (1999) 25:231–240.[CrossRef][Web of Science][Medline]
  64. Lee WY, et al. Modulation of interleukin-1 alpha mRNA expression in mouse epidermis by tumor promoters and antagonists. Mol. Carcinog. (1993) 7:26–35.[Web of Science][Medline]
  65. Wilgus TA, et al. Chemotherapeutic efficacy of topical celecoxib in a murine model of ultraviolet light B-induced skin cancer. Mol. Carcinog. (2003) 38:33–39.[CrossRef][Web of Science][Medline]
  66. Arnott CH, et al. Expression of both TNF-alpha receptor subtypes is essential for optimal skin tumour development. Oncogene (2004) 23:1902–1910.[CrossRef][Web of Science][Medline]
  67. Suganuma M, et al. Essential role of tumor necrosis factor alpha (TNF-alpha) in tumor promotion as revealed by TNF-alpha-deficient mice. Cancer Res. (1999) 59:4516–4518.[Abstract/Free Full Text]
  68. Murphy JE, et al. IL-1 alpha, innate immunity, and skin carcinogenesis: the effect of constitutive expression of IL-1 alpha in epidermis on chemical carcinogenesis. J. Immunol. (2003) 170:5697–5703.[Abstract/Free Full Text]
  69. Coussens LM, et al. Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis. Genes Dev. (1999) 13:1382–1397.[Abstract/Free Full Text]
  70. de Visser KE, et al. De novo carcinogenesis promoted by chronic inflammation is B lymphocyte dependent. Cancer Cell (2005) 7:411–423.[CrossRef][Web of Science][Medline]
  71. Akhurst RJ, et al. Localized production of TGF-beta mRNA in tumour promoter-stimulated mouse epidermis. Nature (1988) 331:363–365.[CrossRef][Medline]
  72. Cui W, et al. Concerted action of TGF-beta 1 and its type II receptor in control of epidermal homeostasis in transgenic mice. Genes Dev. (1995) 9:945–955.[Abstract/Free Full Text]
  73. Li J, et al. TGF-beta3, but not TGF-beta1, protects keratinocytes against 12-O-tetradecanoylphorbol-13-acetate-induced cell death in vitro and in vivo. J. Biol. Chem. (1999) 274:4213–4219.[Abstract/Free Full Text]
  74. Li AG, et al. Smad3 knockout mice exhibit a resistance to skin chemical carcinogenesis. Cancer Res. (2004) 64:7836–7845.[Abstract/Free Full Text]
  75. Li AG, et al. Latent TGFbeta1 overexpression in keratinocytes results in a severe psoriasis-like skin disorder. EMBO J. (2004) 23:1770–1781.[CrossRef][Web of Science][Medline]
  76. Liu X, et al. Conditional epidermal expression of TGFbeta 1 blocks neonatal lethality but causes a reversible hyperplasia and alopecia. Proc. Natl Acad. Sci. USA (2001) 98:9139–9144.[Abstract/Free Full Text]
  77. Lu SL, et al. Overexpression of transforming growth factor beta1 in head and neck epithelia results in inflammation, angiogenesis, and epithelial hyperproliferation. Cancer Res. (2004) 64:4405–4410.[Abstract/Free Full Text]
  78. Veldhoen M, et al. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity (2006) 24:179–189.[CrossRef][Web of Science][Medline]
  79. Mangan PR, et al. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature (2006) 441:231–234.[CrossRef][Medline]
  80. Peto J. Cancer epidemiology in the last century and the next decade. Nature (2001) 411:390–395.[CrossRef][Medline]
  81. Martinez JC, et al. Defining the clinical course of metastatic skin cancer in organ transplant recipients: a multicenter collaborative study. Arch. Dermatol. (2003) 139:301–306.[Abstract/Free Full Text]
  82. Ullrich SE. Mechanisms underlying UV-induced immune suppression. Mutat. Res. (2005) 571:185–205.[Web of Science][Medline]
  83. Oldfield V, et al. Imiquimod: in superficial basal cell carcinoma. Am. J. Clin. Dermatol. (2005) 6:195–200.[CrossRef][Web of Science][Medline]
  84. Kovach BT, et al. Use of topical immunomodulators in organ transplant recipients. Dermatol. Ther. (2005) 18:19–27.[CrossRef][Medline]
  85. Eklind J, et al. Imiquimod to treat different cancers of the epidermis. Dermatol. Surg. (2003) 29:890–896.[CrossRef][Web of Science][Medline]
  86. Schiller M, et al. Immune response modifiers–mode of action. Exp. Dermatol. (2006) 15:331–341.[CrossRef][Web of Science][Medline]
  87. Patel A, et al. CD4+ T lymphocyte infiltration correlates with regression of a UV-induced squamous cell carcinoma. J. Dermatol. Sci. (1995) 9:12–19.[CrossRef][Web of Science][Medline]
  88. Halliday GM, et al. Spontaneous regression of human melanoma/nonmelanoma skin cancer: association with infiltrating CD4+ T cells. World J. Surg. (1995) 19:352–358.[CrossRef][Web of Science][Medline]
  89. Kaplan DH, et al. Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice. Proc. Natl Acad. Sci. USA (1998) 95:7556–7561.[Abstract/Free Full Text]
  90. Dighe AS, et al. Enhanced in vivo growth and resistance to rejection of tumor cells expressing dominant negative IFN gamma receptors. Immunity (1994) 1:447–456.[CrossRef][Web of Science][Medline]
  91. Smyth MJ, et al. Perforin-mediated cytotoxicity is critical for surveillance of spontaneous lymphoma. J. Exp. Med. (2000) 192:755–760.[Abstract/Free Full Text]
  92. Girardi M, et al. Regulation of cutaneous malignancy by gammadelta T cells. Science (2001) 294:605–609.[Abstract/Free Full Text]
  93. Girardi M, et al. The distinct contributions of murine T cell receptor (TCR)gammadelta+ and TCRalphabeta+ T cells to different stages of chemically induced skin cancer. J. Exp. Med. (2003) 198:747–755.[Abstract/Free Full Text]
  94. Darwiche N, et al. Expression profile of skin papillomas with high cancer risk displays a unique genetic signature that clusters with squamous cell carcinomas and predicts risk for malignant conversion. Oncogene (2007) 26:6885–6895.[CrossRef][Web of Science][Medline]
  95. Torre-Amione G, et al. A highly immunogenic tumor transfected with a murine transforming growth factor type beta 1 cDNA escapes immune surveillance. Proc. Natl Acad. Sci. USA (1990) 87:1486–1490.[Abstract/Free Full Text]
  96. Gorelik L, et al. Immune-mediated eradication of tumors through the blockade of transforming growth factor-beta signaling in T cells. Nat. Med. (2001) 7:1118–1122.[CrossRef][Web of Science][Medline]
  97. Chen W, et al. Conversion of peripheral CD4+. J. Exp. Med. (2003) 198:1875–1886.[Abstract/Free Full Text]
  98. Schramm C, et al. TGFbeta regulates the CD4+CD25+ T-cell pool and the expression of FoxP3 in vivo. Int. Immunol. (2004) 16:1241–1249.[Abstract/Free Full Text]
  99. Piccirillo CA, et al. CD4(+)CD25(+) regulatory T cells can mediate suppressor function in the absence of transforming growth factor beta1 production and responsiveness. J. Exp. Med. (2002) 196:237–246.[Abstract/Free Full Text]
  100. Marie JC, et al. TGF-beta1 maintains suppressor function and FoxP3 expression in CD4+CD25+ regulatory T cells. J. Exp. Med. (2005) 201:1061–1067.[Abstract/Free Full Text]
  101. Chen ML, et al. Regulatory T cells suppress tumor-specific CD8 T cell cytotoxicity through TGF-beta signals in vivo. Proc. Natl Acad. Sci. USA (2005) 102:419–424.[Abstract/Free Full Text]
  102. Liu VC, et al. Tumor evasion of the immune system by converting CD4+. J. Immunol. (2007) 178:2883–2892.[Abstract/Free Full Text]
  103. Xu L, et al. Cutting edge: regulatory T cells induce CD4+CD25-FoxP3- T cells or are self-induced to become Th17 cells in the absence of exogenous TGF-beta. J. Immunol. (2007) 178:6725–6729.[Abstract/Free Full Text]
  104. Halliday GM, et al. Transforming growth factor-beta produced by progressor tumors inhibits, while IL-10 produced by regressor tumors enhances, Langerhans cell migration from skin. Int. Immunol. (2001) 13:1147–1154.[Abstract/Free Full Text]
  105. Weber F, et al. Transforming growth factor-beta1 immobilises dendritic cells within skin tumours and facilitates tumour escape from the immune system. Cancer Immunol. Immunother. (2005) 54:898–906.[CrossRef][Web of Science][Medline]
  106. Uhl M, et al. SD-208, a novel transforming growth factor beta receptor I kinase inhibitor, inhibits growth and invasiveness and enhances immunogenicity of murine and human glioma cells in vitro and in vivo. Cancer Res. (2004) 64:7954–7961.[Abstract/Free Full Text]
  107. Smyth MJ, et al. NKG2D function protects the host from tumor initiation. J. Exp. Med. (2005) 202:583–588.[Abstract/Free Full Text]
  108. Castriconi R, et al. Transforming growth factor beta 1 inhibits expression of NKp30 and NKG2D receptors: consequences for the NK-mediated killing of dendritic cells. Proc. Natl Acad. Sci. USA (2003) 100:4120–4125.[Abstract/Free Full Text]
  109. DasGupta S, et al. Inhibition of NK cell activity through TGF-beta 1 by down-regulation of NKG2D in a murine model of head and neck cancer. J. Immunol. (2005) 175:5541–5550.[Abstract/Free Full Text]
  110. Lee JC, et al. Elevated TGF-beta1 secretion and down-modulation of NKG2D underlies impaired NK cytotoxicity in cancer patients. J. Immunol. (2004) 172:7335–7340.[Abstract/Free Full Text]
Received August 20, 2007; revised September 13, 2007; accepted September 15, 2007.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 J. Cell Sci.Home page
V. L. Martins, J. J. Vyas, M. Chen, K. Purdie, C. A. Mein, A. P. South, A. Storey, J. A. McGrath, and E. A. O'Toole
Increased invasive behaviour in cutaneous squamous cell carcinoma with loss of basement-membrane type VII collagen
J. Cell Sci., June 1, 2009; 122(11): 1788 - 1799.
[Abstract] [Full Text] [PDF]

Home page
 Sci SignalHome page
A. M. Bode and Z. Dong
Signal Transduction Molecules as Targets for Cancer Prevention
Sci. Signal., February 24, 2009; 2(59): mr2 - mr2.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
W. Deng, S. W. Tsao, Y. K. Kwok, E. Wong, X. R. Huang, S. Liu, C. M. Tsang, H. Y.S. Ngan, A. N.Y. Cheung, H. Y. Lan, et al.
Transforming Growth Factor {beta}1 Promotes Chromosomal Instability in Human Papillomavirus 16 E6E7-Infected Cervical Epithelial Cells
Cancer Res., September 1, 2008; 68(17): 7200 - 7209.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
29/1/9    most recent
bgm215v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (3)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Glick, A. B.
Right arrow Articles by Mohammed, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Glick, A. B.
Right arrow Articles by Mohammed, J.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?