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p53, chemokines, and squamous cell carcinoma
David M. Owens
Departments of Dermatology and Pathology, Columbia University College of Physicians and Surgeons, New York, New York, USA.
Address correspondence to: David M. Owens, Department of Dermatology, Columbia University College of Physicians and Surgeons, 630 West 168th Street, VC15-202, New York, New York 10032, USA. Phone: (212) 851-4544; Fax: (212) 851-4540; E-mail: do2112@columbia.edu.
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Published July 2, 2007 - More info
J Clin Invest. 2007;117(7):1752–1755. https://doi.org/10.1172/JCI32719.
© 2007 The American Society for Clinical Investigation
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Abstract
A subset of CC chemokines, acting through CC chemokine receptors (CCRs) 1 to 5, is instrumental in shaping inflammatory responses. Recently, we and others have demonstrated that the atypical chemokine receptor D6 actively sequesters and destroys many of these proinflammatory CC chemokines. This is critical for effective resolution of inflammation in vivo. Inflammation can be protumorigenic, and proinflammatory CC chemokines have been linked with various aspects of cancer biology, yet there is scant evidence supporting a critical role for these molecules in de novo tumor formation. Here, we show that D6-deficient mice have increased susceptibility to cutaneous tumor development in response to chemical carcinogenesis protocols and, remarkably, that D6 deletion is sufficient to make resistant mouse strains susceptible to invasive squamous cell carcinoma. Conversely, transgenic D6 expression in keratinocytes dampens cutaneous inflammation and can confer considerable protection from tumor formation in susceptible backgrounds. Tumor susceptibility consistently correlated with the level of recruitment of T cells and mast cells, cell types known to support the development of skin tumors in mice. These data demonstrate the importance of proinflammatory CC chemokines in de novo tumorigenesis and reveal chemokine sequestration by D6 to be a novel and effective method of tumor suppression.
Authors
Robert J.B. Nibbs, Derek S. Gilchrist, Vicky King, Antonio Ferra, Steve Forrow, Keith D. Hunter, Gerard J. Graham
Abstract
Mutations in ras and p53 are the most prevalent mutations found in human nonmelanoma skin cancers. Although some p53 mutations cause a loss of function, most result in expression of altered forms of p53, which may exhibit gain-of-function properties. Therefore, understanding the consequences of acquiring p53 gain-of-function versus loss-of-function mutations is critical for the generation of effective therapies for tumors harboring p53 mutations. Here we describe an inducible mouse model in which skin tumor formation is initiated by activation of an endogenous K-rasG12D allele. Using this model we compared the consequences of activating the p53 gain-of-function mutation p53R172H and of deleting the p53 gene. Activation of the p53R172H allele resulted in increased skin tumor formation, accelerated tumor progression, and induction of metastasis compared with deletion of p53. Consistent with these observations, the p53R172H tumors exhibited aneuploidy associated with centrosome amplification, which may underlie the mechanism by which p53R172H exerts its oncogenic properties. These results clearly demonstrate that p53 gain-of-function mutations confer poorer prognosis than loss of p53 during skin carcinogenesis and have important implications for the future design of therapies for tumors that exhibit p53 gain-of-function mutations.
Authors
Carlos Caulin, Thao Nguyen, Gene A. Lang, Thea M. Goepfert, Bill R. Brinkley, Wei-Wen Cai, Guillermina Lozano, Dennis R. Roop
Nonmelanoma skin cancer (NMSC) is the most common type of human malignancy, with over one million new cases in the United States annually (1–3). NMSC includes basal cell carcinoma and squamous cell carcinoma (SCC), with SCCs constituting approximately 20% of all NMSCs. In contrast to basal cell carcinomas, SCCs characteristically exhibit a high propensity for invasion and metastasis and may be lethal (1, 2). While the genetic and epigenetic events associated with SCC pathogenesis have been extensively studied, no resulting therapeutic approaches have been generated for the prevention or treatment of this potentially lethal disease. This, coupled with the escalating incidence of NMSC over the last few decades, has made this disease a major public health issue.
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The p53 oncogene: implications for cutaneous SCC
It is widely accepted that genetic insults are indispensable in the formation of a frank tumor. In the development of human cutaneous SCCs, alterations in ras genes (10%–30% incidence) (3, 4) and the p53tumor suppressor gene (40%–50% incidence) (5, 6) have been most heavily implicated. While the majority of these lesions are missense mutations, the functional assessment of p53 missense mutations is complicated in that some give rise to a loss-of-function or null phenotype classically associated with tumor suppressor genes, whereas the majority of p53 missense mutations appear to result in a gain-of-function phenotype. While the presence of both types of p53 mutations in SCCs denotes a selection advantage to these genetic lesions, whether gain-of-function or loss-of-function mutations are more critical for SCC development is unclear. Therefore, the understanding of p53 phenotype status, i.e., tumor suppressive versus oncogenic, as it relates to SCC formation and progression is of paramount importance for the development of relevant therapeutic approaches that target this gene.
In this issue of the JCI, Caulin and coworkers (7) address this problem with an elegant transgenic mouse skin model that delivers allelic doses of oncogenic K-ras (8) in combination with either p53 gain-of-function or null mutations under the regulatory control of an inducible Cre recombinase and targeted to the proliferative layer of the epidermis by the cytokeratin K5 promoter. Using this approach, the authors clearly show that certain p53 missense mutations occurring in human SCCs demonstrate gain-of-function properties in vivo and that p53 gain-of-function mutations accelerate both the frequency and progression of SCCs genetically initiated with oncogenic ras. For over a decade, the conventional regulation of cutaneous SCC by p53 tumor suppressor function was based on the observation that reductions in p53 typically do not increase the frequency or incidence of tumor formation but rather increase the frequency of malignant conversion to SCC (9). The current study confirms this traditional role for loss-of-function p53 mutations in malignant conversion to SCC and also provides completely novel roles for gain-of-function mutant p53 in the early stages of benign papilloma formation and during late-stage metastasis (Figure 1). What is most striking about this study is the accelerated malignant progression, genomic instability, and incidence of metastasis in cells harboring p53 gain-of-function mutations versus p53-null cells. These results indicate that p53 has potent oncogenic properties, and in addition to the p53 mutation spectra that result in the null phenotype critical for conversion to SCC, Caulin et al. have now demonstrated that p53 gain-of-function mutations may actually shift the epigenetic environment of an SCC cell toward that of a highly malignant spindle cell phenotype. Spindle cell tumors, while rarely observed in mouse skin carcinogenesis models, represent the most advanced stage of SCC, are composed almost entirely of undifferentiated cells, and characteristically exhibit a highly aggressive and invasive behavior. Since p53 gain-of-function mutants are transcriptionally active in vitro (10), further studies are needed to identify the potential therapeutic targets within the unique mRNA pool that is maintained by these gain-of-function mutants in vivo. As noted by the authors, a relatively high number of cells harboring p53 missense mutations exist in sun-exposed human epidermis but ultimately never result in SCC formation (6). This supports the multi-hit carcinogenesis model and the hypothesis that additional genetic alterations are required for the development of SCC. However, future studies that allow for more precise targeting of p53 gain-of-function mutations in the epidermis may also illustrate the importance of target cell phenotype, i.e., stem cell versus progenitor or transit amplifying cell, in p53-driven SCC formation.
Figure 1Impact of p53 gain-of-function versus null mutations in epidermal carcinogenesis. In this issue of the JCI, Caulin et al. (7) compare the impact of p53 gain-of-function (G-o-F) versus loss-of-function (L-o-F) mutations in multistage skin carcinogenesis progressing from normal epidermis (i) to initiated epidermis (ii), benign papillomas (iii), malignant SCC (iv), and finally lymph node metastasis (v). p53 gain-of-function mutations effectively stimulate early and late stages of epidermal carcinogenesis, whereas null mutations primarily influence malignant conversion to SCC. Light blue cells, initiated cells containing ras and/or p53 mutations; dark blue cells, metastatic cells; thin arrow, inducer; bold arrow, strong inducer; dotted arrow, little to no effect; asterisk, data previously demonstrated by Kemp et al. (9). PAH, polycyclic aromatic hydrocarbon.
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D6: an atypical chemokine receptor
In general, the relationship between inflammation and cancer has been well documented, from the influence of chronic inflammatory agents on neoplastic cell proliferation in founding a tumor to later stages of tumor progression associated with immune suppression, and clearly indicates that both innate and adaptive responses of the immune system are deeply rooted in cancer cell growth, progression, and migration (11).
A link between skin inflammation and SCC formation was reported as early as 1828 as Marjolin ulcer (12), where SCC development was observed at sites of chronic skin inflammation induced by thermal injury. More recently, the association between SCC development and inflammation has been extended to several human skin pathologies associated with ulceration and further substantiated in a number of transgenic murine skin carcinogenesis models (see ref. 13 for an excellent review), collectively indicating that chronic inflammatory stimuli may be a driving force for epidermal neoplastic cell progression. Despite these efforts, very few studies have surfaced that identify specific inflammatory molecules that are required for de novo skin carcinogenesis (14–16).
In this issue of the JCI, Nibbs and coworkers (17) have assessed the requirement of the atypical chemokine receptor D6 in chemically induced skin inflammation and SCC formation. Previously, this group and others have shown that D6 regulates skin inflammatory responses by reducing the bioavailability of inflammatory chemokines (18), and in the present study they postulate that the sequestration of inflammatory chemokines by D6 is essential to suppressing epidermal carcinogenesis. To support their hypothesis, they show that D6-deficient mice are acutely sensitive to chemically induced SCC formation and in doing so provide the first in vivo evidence that chemokine sequestration is essential for suppressing cutaneous SCC (17). The phenotypic response of D6-deficient mice to acute treatment with the irritant phorbol ester is consistent with the reported role for this receptor in the regulation of heightened inflammatory chemokine levels (18). Their findings in experimental mouse skin carcinogenesis were corroborated by the induction of D6 in lymphatic endothelial cells in close proximity to invasive SCC cells from human oral SCCs. In their model, production of the proinflammatory CC chemokine ligand 3 (CCL3) is prolonged in D6-deficient skin after treatment with phorbol ester, leading to chronic recruitment of two cell types known to be involved in cutaneous SCCs, CD3+ T cells and dermal mast cells (Figure 2). In the absence of D6 chemokine sequestration, the exacerbation of the proinflammatory epidermal microenvironment sensitizes the epidermis to hyperproliferation and ras-driven tumor formation (Figure 2). Finally, the persistence of the proinflammatory chemokine response maintains chronic recruitment of lymphocytes and mast cells and stimulates SCC invasion and metastasis (Figure 2). According to this model, the ability of a particular inflammatory agent to overcome the threshold of normal D6-mediated CCL3 interception should directly correlate with tumor-promoting capability.
Figure 2D6-mediated chemokine sequestration as a threshold barrier for cutaneous SCC. (i) Basal cells in the interfollicular epidermis and hair follicles sustain mutations (light blue cells) due to exposure to UV radiation, chemical carcinogens, viruses, and other pathogens; however, without epigenetic intervention, most of these mutations will lay dormant. (ii) Repeated skin irritation or wounding can heighten inflammatory chemokine levels over that which can be sustained through interception by the D6 receptor (expressed by lymphatic endothelial cells [LECs] in the dermis), resulting in the exacerbated levels of mast cells and T lymphocytes critical for stimulating benign papilloma formation. (iii) In the chronic situation, high levels of immune cells are maintained in the skin and enhance malignant conversion and metastasis of neoplastic epidermal cells (dark blue).
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