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Clinical Cancer Research Vol. 8, 2067-2072, July 2002
© 2002 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

Suppression of Type I Interferon Signaling Proteins Is an Early Event in Squamous Skin Carcinogenesis1

John L. Clifford2, Eugene Walch, Xiulan Yang, Xiaochun Xu, David S. Alberts, Gary L. Clayman, Adel K. El-Naggar, Reuben Lotan and Scott M. Lippman

Departments of Clinical Cancer Prevention [J. L. C., E. W., X. Y., X. X., G. L. C., S. M. L.], Pathology [A. K. E-N.], Head and Neck Surgery [G. L. C.], and Thoracic/Head and Neck Medical Oncology [R. L.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030; Department of Medicine and Pharmacology, Arizona Cancer Center, [D. S. A.] Tucson, Arizona 85724


   ABSTRACT
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 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
Purpose: IFN-based therapy has been shown to be active in the treatmentof squamous cell carcinoma (SCC) of the skin, the most aggressive form of non-melanoma skin cancer. Based largely on this activity, we began programmatically examining the expression of IFN-stimulated gene factor 3 (ISGF-3) proteins (signal transducers and activators of transcription 1{alpha}/ß, signal transducers and activators of transcription 2, and p48), which are important mediators of IFN-{alpha} signaling, in skin premalignancy and SCC. Our previous preliminary studies suggested suppression of some or all of the ISGF-3 proteins in skin SCC.

Experimental Design: To determine the timing of the suppression of IFN-{alpha} signaling proteins in squamous skin carcinogenesis, we have now compared ISGF-3 expression by immunohistochemical staining in biopsies of actinic keratosis, a form of skin premalignancy, and matched normal skin.

Results: We observed a significant decrease in expression of one or more ISGF-3 proteins in 76% of patients with actinic keratosis (19 of 25 patients). In addition, we found a suppression of one or more ISGF-3 proteins in 67% of skin SCC patients tested (12 of 18 patients), confirming our previous observations.

Conclusions: These data have led to the hypothesis that the suppressed expression of ISGF-3 proteins and consequent reduction in responsiveness to endogenous IFN likely are an early event in skin carcinogenesis.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 REFERENCES
 
Non-melanoma skin cancer is the single most commonly diagnosed cancer in the Caucasian population, with >1,000,000 new cases reported in the United States each year (1) . Of the two most common forms of skin cancer (SCC3 and basal cell carcinoma), SCC is clinically the most aggressive, accounting for most of the non-melanoma skin cancer deaths, and has been increasing in incidence since the 1960s, with especially increased rates in recent years. Currently, successful treatment of locally advanced skin SCC involves surgery and radiotherapy. However, aggressive SCC lesions recur at a high rate. AK is a premalignant condition, or IEN, of the skin characterized by keratinocytic atypia, which lies along the causal pathway between normal skin and SCC (2 , 3) . Thus, genetic or epigenetic alterations leading to AK formation can be considered early events in skin carcinogenesis.

IFNs are cytokines that regulate proliferation, differentiation, and immune function (4) . Type I IFNs (IFN-{alpha} and -ß) both bind to cell surface receptors composed of two distinct subunits: IFN-{alpha} receptor 1 and IFN-{alpha} receptor 2. The receptors activate associated kinases, Janus kinase 1 and tyk2, members of the Janus kinase family of receptor-associated tyrosine kinases. These kinases then phosphorylate several different STATs, members of a family of latent cytoplasmic transcription factors, resulting in their translocation to the nucleus, where they can modulate the transcription of several genes (5) . Although they are not the only STATs activated by type I IFNs, STAT1 and STAT2 are likely the most important STATs mediating type I IFN effects and are phosphorylated on tyrosines 701 and 690, respectively (4) . The phosphorylated (activated) STAT1 and STAT2 proteins complex with a third protein, p48, to form the ISGF-3 transcription factor (6) . After translocation to the nucleus, the p48 component of the ISGF-3 binds to DNA sequences called IFN-stimulated response elements, found in the promoters of most type I IFN-responsive genes (6) .

IFN-based therapy has been used successfully for the treatment of several malignancies (7) , including SCC of the skin, with greater activity in premalignancies and locally advanced SCC than in metastatic disease (8 , 9) . Based on this activity and the established roles of ISGF-3 proteins in mediating IFN effects, we began to programmatically study the expression pattern of type I IFN signaling proteins in skin SCC. We previously reported our findings of a suppressed expression of some or all of these proteins in patient samples of aggressive skin SCC relative to adjacent NM epithelium for the majority of a limited number (n = 12) of patients (10) . In the present study, we compared ISGF-3 expression in AKs with that in matched normal skin biopsies to determine whether altered ISGF-3 expression is potentially an early event in skin carcinogenesis. This determination can advance our molecular understanding of the early events in skin cancer development, which is crucial for chemoprevention in this setting (3 , 11) . We also extended our earlier preliminary observation of ISGF-3 protein suppression in aggressive skin SCC to a larger number of patient samples.


   Materials and Methods
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 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Surgical Specimens.
Surgical specimens of AK were obtained from sun-exposed areas of skin from Caucasian patients (ages range, 46–92 years). AK specimens were removed surgically or by shave biopsy, and matched normal skin samples were removed from a distant non-sun-exposed site by punch biopsy. Baseline surgical specimens of aggressive skin SCC came from a Phase III trial of IFN-based therapy (National Cancer Institute CA88233). Aggressive tumors were defined as having met one or more of the following criteria: (a) size >= 2 cm diameter; (b) perineural invasion; (c) nodal involvement; or (d) deep structure (e.g., muscle) involvement. SCC specimens were selected to include tumor and adjacent NM tissue. All specimens were processed by a routine fixation in 10% neutral Bouin’s fixative and embedded in paraffin. All specimens were cut to 4-µM sections and attached to lysine-coated slides.

Immunostaining of Paraffin Sections.
Handling of sections, antigen retrieval, antibodies, and staining conditions were as described previously (10) , with the addition of a pan-cytokeratin antibody (Sigma) that served as a positive staining control. For each antibody, the entire set of AK and matched normal or SCC specimens was processed and immunostained at the same time. The specificity of the antibodies was further verified by Western blotting (data not shown). To control for nonspecific binding of primary antibodies, duplicate samples were incubated with the STAT1{alpha}/ß, STAT2, and p48 antibodies along with either the corresponding immunizing peptides or an irrelevant peptide. In all cases, the immunizing peptide and not the irrelevant peptide blocked staining (Ref. 10 ; data not shown). Duplicate control specimens receiving only second antibody did not stain. Slides were photographed at x200 magnification under oil immersion with a Nikon digital camera.

Densitometric Quantitation of Protein Expression.
Digital images of normal skin, adjacent NM skin, AK, and SCC were captured under identical light intensity, exposure time, and camera settings with a Photometrics Quantix charge-coupled device camera at x200 magnification, using a blue filter, essentially as described previously (10) . Image files were analyzed with IPLabs quantitation software. Three different fields were chosen randomly for normal skin, adjacent NM skin, AK, and SCC and averaged for each specimen. Note that counterstaining was omitted to allow densitometric quantitation of only the brown color of the converted diethyl amino benzene peroxidase substrate.


   Results
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 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 REFERENCES
 
ISGF-3 Protein Expression Is Reduced in AKs Compared with Normal Skin.
To determine whether the suppression of ISGF-3 is an early event in skin cancer progression, we have extended our studies to include comparison of the expression of these proteins in AKs with that in normal skin for 25 subjects. As observed previously for SCCs, there is a decrease in expression of all three ISGF-3 proteins in AKs relative to matched biopsies of normal sun-exposed skin, as determined by immunohistochemical staining (Fig. 1Citation , Normal Skin and Actinic Keratosis). Staining with all three antibodies was primarily cytoplasmic, as would be expected for the ISGF-3 proteins in unstimulated cells. A pan-cytokeratin antibody, which should bind strongly to several keratins in any keratinizing epithelia, was used to control for the quality of the samples (Fig. 1Citation , Pan-cyto). The staining intensity varied greatly from cell to cell in the AK samples but could stain as intensely as in the normal skin, indicating that the specimen is intact. For a more precise determination of ISGF-3 protein expression levels, the staining intensity was digitally quantitated for three randomly chosen fields for both AK and normal skin and is expressed as an average fold decrease in expression for all 25 patient samples (Fig. 2Citation , {blacksquare}). The quantitative results of each patient are shown in Table 1Citation , where numbers indicate the mean antibody stain intensity/pixel (unit area) for three measurements. The surface areas, or volumes, of normal skin and AK cells are similar (Fig. 1Citation , compare Normal Skin and Actinic Keratosis), and hence the numbers are an accurate reflection of the differences in protein levels/cell between these cell types. Of the 19 patients evaluable for all three proteins, 14 (74%) showed a suppression of at least one of the proteins in AK versus normal skin (Table 1)Citation .



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  		Fig. 1. ISGF-3 proteins are suppressed in AK relative to normal skin to a degree similar to aggressive SCC. Thin sections (4-µM) of paraffin-embedded biopsy specimens were immunohistochemically stained with antibodies for the indicated proteins. Normal Skin indicates skin biopsy material taken from a distant non-sun-exposed site. Actinic Keratosis is from sun-exposed skin from the same patient. SCC indicates biopsy material from an aggressive skin SCC taken from a different patient than the samples in the other columns. Pan-cyto indicates staining with a pan-cytokeratin antibody control. All images were photographed at identical magnification (x200).

 


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  		Fig. 2. Densitometric quantitation of antibody staining. Slide images were quantitated as described in "Materials and Methods." {blacksquare}, average fold decrease in staining intensity comparing AK with matched normal skin for each of the indicated proteins for the patients listed in Table 1Citation . {square}, average fold decrease in staining intensity comparing SCC with adjacent NM skin for the patients listed in Table 2Citation .

 

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  		Table 1 ISGF-3 expression in AK compared with matched normal skin

 
ISGF-3 Suppression in Skin SCC.
To confirm our previous observation of ISGF-3 suppression in aggressive skin SCC, we have analyzed SCC biopsies taken at baseline from an additional 18 patients on the study by immunohistochemistry (see "Materials and Methods"). A typical staining for serial sections of aggressive skin SCC is shown in Fig. 1Citation , SCC. Note that the SCC sample is from a different patient than the paired normal skin and AK samples in Fig. 1Citation . Of the 16 patients evaluable for all three proteins, 11 (69%) showed a statistically significant suppression of at least one protein (Table 2)Citation . The average fold decrease in expression for all three proteins was similar for SCC and AK (Fig. 2Citation , compare {square} for SCC with {blacksquare} for AK). The total protein decreases in SCCs probably are not as great (versus normal cells) as the numbers in Table 2Citation indicate because of the generally larger surface area (and volume) of SCC cells (compare Normal Skin and SCC in Fig. 1Citation ). As suggested by the similar per-unit staining intensities between SCCs and AKs, however, ISGF-3 concentration may be more relevant biologically than the total protein content/cell.


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  		Table 2 ISGF-3 expression in aggressive SCC compared with adjacent NM skin

 

   Discussion
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 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
REFERENCES
 
Our present study confirms and extends our preliminary ISGF-3 study in 12 skin SCC patients. Reduced ISGF-3 expression in the 18 currently reported skin SCC patients confirms our previous results and brings the total number of skin SCC patients analyzed to 30. The present study extends the earlier findings by assessing the timing of ISGF-3 protein suppression. We provide the first report of expression of the ISGF-3 proteins in human AK, a form of skin premalignancy, or IEN. ISGF-3 protein expression is suppressed in AK in a manner similar to its suppression in SCC, suggesting that reduced expression is an early event in skin carcinogenesis. This important finding in skin IEN advances our molecular understanding of early skin carcinogenesis, which is crucial to skin cancer chemopreventive drug development (3 , 11) .

The present study was conducted in close conjunction with an ongoing Phase III trial of IFN-based therapy in skin SCC (National Cancer Institute CA88233). The working hypothesis for our ongoing translational IFN studies is that pharmacological doses of IFN-{alpha} may overcome reduced responsiveness to endogenous IFN-{alpha} by saturating the existing signaling machinery, thereby restoring normal IFN-{alpha} responses. This hypothesis is analogous to that proposed for RA signaling in head and neck and skin carcinogenesis, which has been correlated with reductions in RA-signaling proteins (12 , 13) . In addition to its activity in clinical trials for skin AK and SCC (7, 8, 9) , it is well established that RA can suppress skin tumorigenesis in mouse models (14) . This led to a similar hypothesis to the one we now propose for IFN-{alpha}, that pharmacological levels of RA can overcome the reduced RA responsiveness caused by the reduction of RA receptor expression (12 , 13) . The future completion of our ongoing Phase III trial will allow us to assess ISGF-3 levels in IFN-{alpha}-treated versus untreated patients. We also plan to assess levels of IFN-{alpha}-regulated genes, such as IRF-7 and MxA1, to more directly measure IFN-{alpha} responsiveness in this setting.

A role for IFN-{alpha}/ß signaling in skin cancer progression is not clear at present. Previous studies have shown that IFN-{alpha} and IFN-ß can suppress the proliferation of keratinocytes (15) , and a requirement for STAT1 activation for the antiproliferative effects of IFN-{alpha} has been demonstrated (16) .4 STAT1 activation is also required for the apoptotic effect of tumor necrosis factor {alpha} (17) . Suppression of STAT1 protein in SCC cells may therefore result in a loss of both the normal control of proliferation and regulation of apoptosis.

IFN-{alpha}/ß can suppress the tumorigenic phenotype in vitro and in nude mice, and at least part of this effect is due to suppression of angiogenesis (Refs. 18 and 19 and the references therein). Of interest are recent studies on human epidermal cells demonstrating that IFN-ß expression is highest in differentiated, nondividing cells and that SCC cells express lower levels of IFN-ß than normal skin (20) . Those investigators hypothesize that IFN-ß acts as a suppressor of proliferation and angiogenesis, such that its absence would result in a tumorigenic phenotype; i.e., uncontrolled growth and neovascularization. Our findings are compatible with such a role for IFN-{alpha}/ß and further suggest that a decrease IFN responsiveness may similarly lead to tumorigenicity.

IFN-{alpha}/ß also could potentially play a role in tumor surveillance. In a mechanism similar to type I IFN signaling, type II IFN (IFN-{gamma}) activates a distinct set of genes through the formation of STAT1 homodimers (4 , 5) . Kaplan et al. (21) have previously demonstrated that mice lacking either IFN-{gamma} receptors or STAT1 protein develop spontaneous and chemically induced tumors more frequently than wild-type mice. They also demonstrated defects in IFN-{gamma} signaling in several lung adenocarcinoma cell lines, but they did not find similar defects in IFN-{alpha} signaling, leaving a question as to the potential role of IFN-{alpha}/ß in tumor surveillance. Because STAT1 is shared between the type I and type II IFN pathways, our finding that its expression is reduced in human tumors could reflect a defect in both pathways. Whether impaired IFN-{alpha}/ß signaling results in diminished tumor surveillance capacity in skin remains to be investigated.

In conclusion, our novel AK results suggest that suppressed ISGF-3 expression occurs early in skin cancer development and that a reduced response to type I IFNs (IFN-{alpha}/ß) is involved in the earliest stages of skin carcinogenesis. These findings provide a mechanistic rationale for the activity of IFN-{alpha} in skin carcinogenesis and provide provocative leads for new molecular targeting chemoprevention approaches involving ISGF-3 proteins in the skin.


   ACKNOWLEDGMENTS
 
We thank David Menter and other members of the department for helpful discussions and advice. We thank Kendall Morse for critical reading of the manuscript.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported in part by National Cancer Institute Grants 5 R29 CA78560 and 1 P01 CA88233 and National Institute of Environmental Health Sciences Grant 5 P30 ES07784. Back

2 To whom requests for reprints should be addressed, at Department of Clinical Cancer Prevention, The University of Texas M. D. Anderson Cancer Center, Box 236, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: (713) 792-0627; Fax: (713) 792-0628; E-mail: jclifford{at}mdanderson.org Back

3 The abbreviations used are: SCC, squamous cell carcinoma; AK, actinic keratosis; IEN, intraepithelial neoplasia; STAT, signal transducers and activators of transcription; ISGF-3, IFN-stimulated gene factor-3; NM, nonmalignant; RA, retinoic acid. Back

4 J. L. Clifford, E. Walch, X. Yang, C. Zou, M. Wang, R. Lotan, and S. M. Lippman, unpublished results. Back

Received 1/ 9/01; revised 3/11/02; accepted 3/23/02.


   REFERENCES
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 Introduction
 Materials and Methods
 Results
 Discussion
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