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Animal Model |
From the Department of Molecular Pharmacology and The Albert Einstein Cancer Center,* Albert Einstein College of Medicine; the Department of Pathology, Albert Einstein College of Medicine and Montefiore Medical Center; the Divisions of Cardiology and Infectious Disease, Department of Medicine, Albert Einstein College of Medicine and The Montefiore Medical Center; the Department of Pathology, Albert Einstein College of Medicine, Bronx, New York
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Abstract |
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Since then, cell culture experiments have contributed a wealth of evidence suggesting that caveolin-1 may function as a transformation or tumor suppressor. Caveolin-1 mRNA and protein levels are strikingly down-regulated in NIH 3T3 fibroblasts transformed with activated oncogenes such as v-Abl, Bcr-Abl, and H-RasG12V, with their ability to grow in soft agar being inversely correlated with caveolin-1 protein levels.3
Moreover, recombinant expression of caveolin-1 has been shown to inhibit tumor cell proliferation and severely reduces the ability of these cells to proliferate in an anchorage-independent manner.4-8
In a separate report, ablation of caveolin-1 levels using an anti-sense approach was sufficient to induce NIH 3T3 cell transformation, as evidenced by growth in soft agar and the formation of tumors in nude mice.9
These findings appear to be mediated in part through hyperactivation of the Ras-p42/44 MAP kinase cascade and are reversible after loss of the Cav-1 anti-sense vector. Conversely, Lee and colleagues10
have shown that reintroduction of caveolin-1 into a human breast cancer cell line, namely T47D, resulted in an 
50% reduction in proliferation and a remarkable 15-fold decrease in soft agar colony formation. Additionally, other groups have reported that exogenous expression of caveolin-1 dramatically reduces anchorage-independent growth, cell migration, matrix invasion, and lamellipod extension in transformed mammary epithelial cell lines, ie, MCF-7 and MTLn3.7,8
Aside from data derived from cell culture experiments, there are several lines of clinical and genetic evidence implicating caveolin-1 as a tumor suppressor in vivo. First, caveolin-1 maps to the 7q31.1 region on human chromosome 7, which is frequently deleted in a number of human epithelial-derived cancers, including breast, prostate, ovarian, renal, and colon cancers.11-18
This region (D7S522) is also a common fragile site known as FRA7G and is suspected to harbor a tumor suppressor locus.12,19
Second, caveolin-1 levels have been shown to be down-regulated in a number of human-derived cell lines, including mammary adenocarcinomas and in tumors derived from transgenic mouse models of breast cancer.10,20-22
Finally, Hayashi and colleagues have identified a sporadic P132L mutation in the caveolin-1 gene in up to 16% of tumors from a human breast cancer cohort.23
In further support of this clinical finding, we have recently shown that Cav-1 (P132L) behaves in a dominant-negative fashion, causing the intracellular retention of wild-type Cav-1 in the Golgi compartment.24
Using standard homologous recombination techniques, we and others have reported on the generation of caveolin-1 (-/-) deficient mice.25,26 While these mice do not experience an increased rate of spontaneous tumor formation, there are several phenotypes that we have recently described which suggest the dysregulation of cellular proliferation. These include hyperproliferation of cultured mouse embryonic fibroblasts (MEFs), an abnormal hypercellular lung phenotype, and mammary epithelial cell hyperplasia in virgin female mice,24 with the accelerated development of the lobular-alveolar compartment during pregnancy and premature lactation.27 However, there have been no studies to directly document whether loss of caveolin-1 predisposes mice to tumor formation either by chemically-induced carcinogenesis or by breeding them to genetic tumor-prone mouse models.
Therefore, to more directly examine the role of caveolin-1 in tumor formation, we subjected Cav-1 (-/-) null mice, and their wild-type littermates, to a skin carcinogenesis protocol using 7,12-dimethlybenzanthracene (DMBA). Chemical carcinogenesis induced by DMBA is a well-documented method for generating skin tumors in mice.28-32 DMBA is a genotoxic agent that forms DNA adducts resulting in DNA damage and genomic instability leading to tumor initiation. Here, we report that loss of caveolin-1 gene expression sensitizes mouse skin to carcinogen-induced epidermal hyperplasia and tumorigenesis in vivo. These findings clearly provide the first in vivo evidence that caveolin-1 can function either as a tumor suppressor or a tumor susceptibility gene.
In support of these findings, Gumbleton and colleagues examined the expression pattern of caveolin-1 in chronic plaque psoriasis, a well-known hyperproliferative skin disorder.33 They showed that caveolin-1 expression was greatly reduced or absent in the hyperproliferating basal cell layer of human psoriatic plaques. Based on these data, they hypothesized that down-regulation of caveolin-1 expression may be a critical factor in the pathogenesis or progression of psoriasis. Consistent with this correlative data, we directly show that loss of caveolin-1 gene expression predisposes murine keratinocytes toward epidermal hyperplasia.
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Materials and Methods |
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Antibodies and their sources were as follows: anti-caveolin-1 IgG (rabbit pAb; Santa Cruz Biotechnology, Inc., Santa Cruz, CA); anti-mouse keratin-10 IgG (rabbit pAb; Covance Research Products, Inc., Princeton, NJ); anti-mouse keratin-14 IgG (rabbit pAb; Covance Research Products, Inc.); anti-phospho-ERK-1/2 IgG (rabbit pAb; Cell Signaling, Inc., Beverly, MA); and anti-cyclin D1 IgG (rabbit pAb; NeoMarkers, Inc., Fremont, CA). A variety of other reagents were purchased commercially and were the highest purity grade available.
Generation and Husbandry of Caveolin-1 Null Mice
Cav-1 (-/-) knockout mice were generated as previously described, using standard homologous recombination techniques.26 All animals used for these experiments (Cav-1 null mice and their wild-type control littermates) were in the C57Bl/6 background. Mice were housed and maintained in a barrier facility at the Albert Einstein College of Medicine, Bronx, New York. Mice were kept on 12-hour light/dark cycle and they had ad libitum access to chow (Picolab 20; PMI Nutrition International) and water.
Transmission Electron Microscopy
Skin biopsies from the backs of untreated wild-type and Cav-1 null mice were fixed with 2.5% glutaraldehyde/0.1 mol/L cacodylate, postfixed with OsO4, and stained with uranyl acetate and lead citrate. Samples were then examined under a JEOL 1200EX transmission electron microscope and photographed at a magnification of 16,000x. Caveolae were identified by their characteristic flask-like shape, size (50 to 100 nm), and location proximal to the plasma membrane.
Induction of Tumorigenesis
Skin carcinogenesis was induced essentially as previously described.30,34 Briefly, a total of 30 mice were used (Cav-1 +/+, n = 15; Cav-1 -/-, n = 15). The backs of 6-day-old mice were shaved and painted once a week with a solution of 0.5% DMBA (7,12-dimethylbenzanthracene; Sigma, St. Louis, MO) dissolved in acetone. Mice were monitored weekly for the appearance of tumors. For calculation of tumor area per mouse, the size of tumors was measured using a caliper and the total area of the tumors was then calculated and divided by the number of mice analyzed.
Collection and Processing of Skin and Tumor Samples
Mice were sacrificed and skin biopsies or tumors were surgically removed and fixed in 10% neutral-buffered formalin for 24 hours, after which the samples were placed in 70% ethanol until processing. Tissue samples were paraffin-embedded, 4- to 5-µm sections were cut, and placed on Super Frost Plus slides (Fisher) for pathological evaluation or immunostaining.
Histopathological Analyses
For tumor evaluation and classification, H&E tissue sections were microscopically examined at low and high magnification by Dr. Steve McClain, an expert dermato-pathologist.
Immunostaining of Tissue Sections
For immunostaining, paraffin-embedded tissue sections were de-paraffinized in xylene (twice, 10 minutes each), dehydrated through a graded series of ethanol washes, and placed in PBS. After use of an Antigen Retrieval Kit (DAKO Corp), tissue sections were blocked with 5% fetal bovine serum in PBS for 30 minutes at room temperature. Primary antibodies were used at the following dilutions: anti-caveolin-1 pAb (1:1000); anti-mouse keratin-10 (1:1000); and anti-mouse keratin-14 (1:10,000), in PBS containing 0.1% BSA. Fluorescently conjugated secondary antibodies (5 µg/ml) were added to the sections for 30 minutes at room temperature. After extensive washing with PBS, the slides were mounted with Slow-Fade anti-fade reagent (Molecular Probes). Slides were observed with an Olympus IX 70 inverted microscope.
Similar experiments were carried out using primary antibodies directed against cyclin D1 and phopho-ERK1/2, and HRP-conjugated secondary antibodies. However, endogenous peroxide activity was quenched by incubating the slides for 10 minutes in 1% H2O2. Bound antibodies were visualized using DAB as the substrate (for 15–20 seconds). Finally, the slides were washed in dH2O to remove excess DAB, counterstained with hematoxylin, dehydrated, and mounted with coverslips.
Statistical Analyses
Results are represented as the mean ± SEM. Statistical significance was determined using Student’s t-test, with P < 0.05 being considered significant.
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Results |
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To assess the morphology of the epidermis in Cav-1 null mice, skin biopsies were taken and fixed in formalin. After H&E staining, the paraffin-embedded sections were analyzed by light microscopy. Figure 1
shows the morphology of skin samples derived from the backs of adult Cav-1 null mice and their corresponding wild-type controls (all 4 months old). Note that the epidermal layer appears normal; importantly, no epidermal hyperplasia was evident in Cav-1 null mouse skin.
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(left panel) shows that caveolin-1 is robustly expressed in murine keratinocytes, especially within the basal cell layer (see arrow) and the hair follicles (see asterisks). Similarly, other groups have shown that caveolin-1 is normally expressed at high levels in human keratinocytes, especially within the basal cell layer.33,35,36
In contrast, skin tissue sections derived from Cav-1 null mice show no caveolin-1 immunostaining, as expected (Figure 2
, right panel).
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shows by transmission electron microscopy that Cav-1 null keratinocytes lack morphologically identifiable caveolae membranes, while wild-type keratinocytes have abundant plasmalemmal caveolae.
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, and were virtually absent from the lateral and apical surfaces. Consistent with these findings, a similar polarized distribution of caveolin-1 and caveolae has been noted in both renal and intestinal epithelial cells.37-39 Cav-1 Null Mice Are Dramatically More Susceptible to DMBA-Induced Skin Carcinogenesis
To assess the tumor suppressor role of caveolin-1 in a whole animal model, we treated the skin of Cav-1 null mice and their wild-type counterparts with a known carcinogen, DMBA (7,12-dimethylbenzanthracene), using a standard protocol. DMBA treatments were administered weekly for a period of up to 16 weeks and tumor appearance was monitored visually.
Figure 4A
shows that the tumor incidence in Cav-1 null mice is greatly increased. At 8 weeks of treatment, only 10% of wild-type mice developed tumors and this remained constant for up to 16 weeks. In striking contrast, at 8 weeks of treatment, > 80% of Cav-1 null mice developed tumors, reaching 100% at 12 weeks. Thus, at 16 weeks of treatment, Cav-1 null mice show a 10-fold increase in tumor incidence. Figure 4B
shows that tumor multiplicity is also greatly increased in Cav-1 null mice. For example, at 8 and 12 weeks of treatment Cav-1 null mice show an 10-fold increase in tumor number per mouse. In addition, at 16 weeks of treatment, Cav-1 null mice show an 15-fold increase in tumor multiplicity.
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shows an 35-fold increase in tumor area per Cav-1 null mouse.
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. After 16 weeks of treatment, tumors and their adjacent normal tissue were excised and subjected to histopathological analysis. Figure 8
illustrates three such representative lesions that were all classified as noninvasive papillomas, with significant epidermal hyperplasia. One wild-type tumor and two Cav-1 null tumors are shown for comparison. However, tumor grade was not increased in Cav-1 null mice, but the incidence, the multiplicity, and the growth of tumors were increased.
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Because the tumor grade was not increased in Cav-1 null mice, we next examined the morphology of the skin at 7 weeks of DMBA-treatment, just before the development of tumors. Skin tissue samples were excised, formalin-fixed, paraffin-embedded, and stained with H&E.
Figure 9
shows medium- and high-power views of treated wild-type and Cav-1 null skin. Note that in wild-type animals, there is only a modest increase in the thickness of the epidermal layer, as compared with non-treated animals (see Figure 1
for comparison). However, in Cav-1 null mice, there is a dramatic increase in the thickness of the epidermal layer, ie, severe epidermal hyperplasia. The change in epidermal thickness is best appreciated at high power (B), while the extent of these changes is best visualized at medium power (A). Note also that all of the layers of the epidermis, especially the basal, granular, and cornified layers are hyperplastic or thickened. Thus, it appears that Cav-1 null mice are more susceptible to DMBA-induced epidermal hyperplasia, possibly explaining their accelerated rate of tumorigenesis.
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clearly shows that in Cav-1 null mice both the suprabasal cell layer (keratin-10 immunostaining, panel A) and the basal cell layer (keratin-14 immunostaining, panel B) are increased in thickness and appear hypercellular. These results directly support the idea that the skin of Cav-1 null mice undergoes significant epidermal hyperplasia in response to DMBA treatment.
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Cav-1 is known to function as a negative regulator of the Ras-p42/44 MAP kinase cascade and as a transcriptional repressor of cyclin D1, possibly explaining its transformation suppressor activity in cultured cells.4,9,41,42 Thus, we next examined the levels of cyclin D1 and activated ERK1/2 during DMBA-induced epidermal hyperplasia. At 7 weeks of DMBA-treatment, just before the development of tumors, skin tissue samples were excised, formalin-fixed, paraffin-embedded and immunostained with antibodies to cyclin D1 and activated ERK1/2.
Figure 11A
shows that in wild-type animals, mainly the proliferative basal cell layer is immunostained for cyclin D1; in contrast, in Cav-1 null animals, both the basal cell layer and the suprabasal layers are heavily immunostained. Similarly, phospho-ERK1/2 immunostaining was clearly elevated in Cav-1 null keratinocytes and notably absent in wild-type keratinocytes (Figure 11B)
. Thus, cyclin D1 and phospho-ERK1/2 levels are up-regulated in Cav-1 null keratinocytes during DMBA-induced epidermal hyperplasia. These findings provide a possible mechanism to explain why Cav-1 null mice are more susceptible to DMBA-induced skin carcinogenesis.
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Discussion |
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What is the role of Cav-1 in skin tumorigenesis? We and others have demonstrated that skin tissue exhibits significant amounts of caveolin-1 expression, including the epidermis, but there is not much known regarding what role caveolin-1 plays in different skin cell types. For the two main caveolar functions that have garnered the most attention, membrane trafficking and signal transduction, a large body of evidence has accumulated supporting a role for caveolin-1 as a negative regulator of cell transformation and tumorigenesis. Indeed, caveolae microdomains are enriched in a number of signaling molecules including H-Ras, Src-family tyrosine kinases, hetero-trimeric G-protein subunits, receptor tyrosine kinases (RTKs; EGF-R, c-Neu, PDGF-R, and insulin receptor), and endothelial nitric-oxide synthase (eNOS), and many of these molecules have been shown to interact directly with caveolin-1 via the caveolin-scaffolding domain (CSD) (reviewed in1 ). These results suggest that caveolins are important signaling modulators within the context of caveolae membranes.
Functionally, it appears that caveolin binding serves to inhibit downstream signaling events. For example, Cav-1 has been shown to interact with and suppress the kinase activity of the EGF receptor and several members of the Ras-p42/44 MAP kinase cascade, including MEK and ERK.41,43 Conversely, down-regulation of Cav-1 by an anti-sense methodology results in hyperactivation of the p42/44 MAP kinase cascade and cellular transformation.9 Moreover, down-regulation of Cav-1 expression by RNAi in Caenorhabditis elegans results in hyperactivation of the meiotic cell cycle, which is controlled by the Ras-MAP kinase pathway.44 In accordance with these findings, we show here that phospho-ERK1/2 levels are up-regulated in Cav-1 null keratinocytes during DMBA-induced epidermal hyperplasia in vivo.
There is also an emerging role for caveolin-1 in cell cycle control. Indeed, the balance between cellular differentiation and proliferation is extremely relevant to the process of tumorigenesis. Besides controlling tumor growth rates, this balance can also determine tumor grade since the most invasive tumors are generally among the most poorly-differentiated morphologically. Cav-1 is highly expressed in well-differentiated and slowly proliferating cell types, such as adipocytes and endothelial cells. Primary mouse embryonic fibroblasts (MEFs) derived from Cav-1 (-/-) null mice proliferate faster, show increased DNA-synthesis rates (thymidine incorporation), and demonstrate an increased percentage of cells in S-phase, as compared to their Cav-1 expressing wild-type counterparts.26
In addition to repression of the Ras-p42/44 MAP kinase pathway, Cav-1 has been found to transcriptionally repress cyclin D1 expression.42 Cyclin D1 is a well-characterized protein that forms complexes with the cyclin-dependent kinases, cdk4 and cdk6, thereby activating them and allowing entry into S-phase. In addition, the cyclin D1 gene is amplified or over-expressed in a number of epidermal-derived tumors, such as human squamous cell carcinomas or mouse epidermal papillomas harboring activated ras genes.45,46 Interestingly, DMBA-treatment of transgenic C57Bl/6 mice with keratinocyte-specific over-expression of cyclin D1 resulted in the appearance of papillomas in 100% of mice after 40 weeks; in contrast, wild-type control mice showed a tumor incidence of only 9.5% under identical conditions.34 Additionally, primary cultured keratinocytes from these cyclin D1 transgenic mice were refractory to calcium-induced terminal differentiation and continued to divide in culture. Thus, in Cav-1 null mice, an absence of transcriptional repression by caveolin-1 could result in overexpression of cyclin D1, providing a possible mechanism for the accelerated appearance of skin papillomas. In support of this prediction, we show here that cyclin D1 levels are up-regulated in Cav-1 null keratinocytes during DMBA-induced epidermal hyperplasia.
There are a number of oncogenes, including H-Ras, v-Abl, middle T antigen, Bcr-Abl, v-Src, Neu T (ErbB2), and c-Myc which target caveolin-1 for transcriptional repression.1 Indeed, one of the first experiments implicating Cav-1 as a target for cell transformation showed that stable expression of activated H-Ras (G12V mutant) in NIH 3T3 cells causes down-regulation of Cav-1 mRNA and protein levels.3 Importantly, down-regulation of Cav-1 was completely reversed by treatment with an inhibitor of the Ras-p42/44 MAP kinase pathway, namely PD 98059.4 Furthermore, recombinant expression of Cav-1 in H-RasG12V-transformed NIH 3T3 cells resulted in abrogation of the transformed phenotype, with dramatic inhibition of the Ras-p42/44 MAP kinase cascade.4 Interestingly, DMBA-induced carcinogenesis often results in papillomas with activating mutations in the H-Ras proto-oncogene (especially at codon 61).47,48 Others have shown that activated Ras can then induce over-expression of cyclin D1.49 Taken together, these data provide an additional mechanism by which loss of caveolin-1 could enhance the initiation of papilloma formation.
Further support for a pro-differentiation or anti-proliferative function for caveolin-1 in skin comes from an in vitro model of keratinocyte differentiation, where others have shown that caveolin-1 protein expression is significantly up-regulated during the differentiation of primary human keratinocytes cultured on a collagen-based matrix.50
Interestingly, caveolin-1 expression was up-regulated by 8-fold in parallel with certain well-known keratinocyte differentiation markers, such as involucrin and fillagrin.50
Thus, caveolin-1 may play a role in suppressing the proliferation of keratinocytes, perhaps facilitating their ability to undergo differentiation. Furthermore, using PCR and subtractive hybridization techniques, caveolin-1 was independently identified as a KGF (keratinocyte growth factor)-regulated gene.35
For example, after KGF treatment of keratinocytes in culture, both caveolin-1 mRNA and protein levels increased dramatically. Similarly, caveolin-2 was also induced in response to KGF treatment. This is in contrast to the finding that treatment of NIH 3T3 fibroblasts with other growth factors (such as PDGF and FGF) leads to the p42/44 MAP kinase-induced suppression of caveolin-1 gene expression.35
In accordance with our current findings, Gumbleton and colleagues33 have recently examined the expression pattern of caveolin-1 in a well-known hyperproliferative skin disorder in humans, chronic plaque psoriasis. In 20 of the 22 patients examined, caveolin-1 expression in the hyperproliferating basal cell layer of psoriatic plaques was greatly reduced or absent. Based on these findings, they postulated that down-regulation of caveolin-1 expression may be a critical factor in the pathogenesis or progression of psoriasis. Consistent with this correlative data, we directly demonstrate that loss of caveolin-1 gene expression predisposes murine keratinocytes toward epidermal hyperplasia if they are provided with the appropriate stimulus.
In conclusion, our results argue that caveolin-1 may indeed play an important role in the suppression of tumor formation. Given a carcinogenic-stimulus, we have shown that loss of caveolin-1 expression by targeted gene-deletion in mice predisposes these animals toward epidermal hyperplasia and accentuates skin tumor initiation, multiplicity, and growth. As such, this study represents the first clear genetic evidence that caveolin-1 can function either as a tumor suppressor or tumor susceptibility gene in an in vivo animal model.
Interestingly, we have recently observed that Cav-1 (-/-) null mice show endothelial-based defects in angiogenesis in vivo (51). Thus, the dramatic increases in DMBA-induced skin tumorigenesis we observe here in Cav-1 (-/-) null mice may actually be an underestimate of the tumor suppressor capacity of caveolin-1.
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Acknowledgements |
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Footnotes |
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Supported by grants from the National Institutes of Health, the Muscular Dystrophy Association, the American Heart Association, and the Breast Cancer Alliance, as well as a Hirschl/Weil-Caulier Career Scientist Award (all to M.P.L.). T.M.W. was supported by a National Institutes of Health Medical Scientist Training Grant (T32-GM07288).
Accepted for publication February 13, 2003.
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