M O L E C U L A R O N C O L O G Y 4 ( 2 0 1 0 ) 1 1 9 – 1 2 5

ava i lab le at www.sc ienced i rec t . com

www.e lsev ie r . com/ loca te /molonc

Positron emission tomography imaging of DMBA/TPA mouse skin

multi-step tumorigenesis

Tomo-o Ishikawaa, Indracanti Prem Kumara, Hidevaldo B. Machadoa, Koon-Pong Wonga,Donna Kusewittb, Sung-Cheng Huanga, Susan M. Fischerb, Harvey R. Herschmana,c,*aDepartment of Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USAbThe University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USAcDepartment of Biological Chemistry, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA

A R T I C L E I N F O

Article history:

Received 15 January 2010

Received in revised form

23 January 2010

Accepted 24 January 2010

Available online 2 February 2010

Keywords:

Glucose metabolism

PET

Skin cancer

Molecular imaging

Fluorodeoxyglucose

* Corresponding author at: 341 Boyer Hall, Ufax: þ1 310 825 1447.

E-mail address: hherschman@mednet.uc1574-7891/$ – see front matter ª 2010 Federdoi:10.1016/j.molonc.2010.01.005

A B S T R A C T

Many tumor cells have elevated rates of glucose uptake that can be measured quantita-

tively, noninvasively and repeatedly by positron emission tomography (PET) with 2-de-

oxy-2-[18F]-fluoro-D-glucose (18F-FDG). Clinical imaging with 18F-FDG PET has been used

for detection and staging of primary and metastatic tumors. High-resolution microPET

scanning and murine cancer models make it possible to analyze longitudinally glucose me-

tabolism during the appearance, development and progression of individual experimental

tumors. In this study, we used 18F-FDG microPET and micro computerized tomography (mi-

croCT) to investigate glucose uptake in the DMBA/TPA chemically-induced multistage

mouse skin carcinogenesis model. 18F-FDG uptake is significantly higher in all papillomas

than in surrounding skin. Elevated 18F-FDG uptake is observed when tumors can be iden-

tified morphologically, but not before. Although 18F-FDG uptake is high in all fully invasive,

malignant skin squamous cell carcinomas, uptake in papillomas and microinvasive malig-

nant squamous cell carcinomas is variable and does not exhibit any correlation with tumor

stage.

ª 2010 Federation of European Biochemical Societies.

Published by Elsevier B.V. All rights reserved.

1. Introduction measured with 18F-FDG PET is largely dependent on the rate

Positron emission tomography (PET) with the glucose ana-

logue 2-deoxy-2-[18F]-fluoro-D-glucose (18F-FDG) positron-

emitting tracer is a widely used clinical imaging technique

to detect primary and metastatic cancers (Phelps, 2000). Nu-

merous 18F-FDG PET studies have demonstrated that most

malignant human tumors show significantly increased 18F-

FDG uptake. Elevated rates of 18F-FDG uptake are also strongly

correlated with poor outcome in many cancers (Gambhir

et al., 2001; Kelloff et al., 2005). The increased tracer uptake

CLA, 611 Charles E. Youn

la.edu (H.R. Herschman).ation of European Bioche

of glycolysis. Injected 18F-FDG is transported through the cell

membrane by glucose transporters and then phosphorylated

by hexokinase to 18F-FDG-6-phosphate. Because 18F-FDG-6-

phosphate cannot be metabolized, and the cell membrane is

not permeable for phosphorylated 18F-FDG, 18F-FDG-6-phos-

phate is trapped and accumulates in cells. When the unphos-

phorylated 18F-FDG has been eliminated from tissues and

blood, from tissues and blood, the accumulation of phosphor-

ylated 18F-FDG can be imaged and quantitatively measured by

PET scanning (Phelps, 2000).

g Drive East, Los Angeles, CA 90095, USA. Tel.: þ1 310 825 8735;

mical Societies. Published by Elsevier B.V. All rights reserved.

M O L E C U L A R O N C O L O G Y 4 ( 2 0 1 0 ) 1 1 9 – 1 2 5120

With the development of high-resolution microPET scan-

ners designed for laboratory animal imaging, the pre-clinical

application of non-invasive imaging of animal models has in-

creased substantially (Herschman, 2003). In vivo imaging of

mouse models of cancer makes it possible to analyze – non-

invasively, quantitatively and repeatedly – the longitudinal

development and progression of individual tumors (Cherry,

2001). Xenograft models of human tumors on immunocom-

promised mice have been widely used for this purpose; how-

ever, several crucial differences exist for such models when

compared either to endogenous tumors in patients or to au-

tochthonous murine tumors. Such differences include, but

are not limited to, tumor architecture, microenvironment, im-

mune modulation and cell autonomous features (Frese and

Tuveson, 2007). In contrast, chemically-induced murine can-

cers in immunocompetent mice are widely used as autoch-

thonous preclinical cancer models in which to study genetic

effects, the role of microenvironment, immune modulation

and alternative therapeutic approaches.

One of the most intensively studied chemically-induced

cancer models is the murine skin carcinogenesis model

(Kemp, 2005). This model exemplifies the three stages of

tumor development; initiation, promotion and progression.

Initiation is generally elicited by the application of a low

dose of carcinogen such as 7,12-dimethylbenz[a]anthracene

(DMBA). This treatment causes an activating, oncogenic mu-

tation of the H-ras gene in skin epithelial cells. Those cells

are promoted by repeated application of a non-carcinogenic

promoter such as 12-0-tetradecanoylphorbol-13-acetate

(TPA). Tumor promoters do not directly change the DNA

sequence, however, they elicit a wide range of cellular and

biochemical changes related to cell growth and differentia-

tion. Initiated cells are expanded by promoter treatment

and develop into premalignant papillomas. The progression

step in DMBA/TPA induced skin cancer is a spontaneous

process facilitated by genetic instability; loss of p53 gene is

frequent. Some papillomas acquire the ability to invade as

a result of the progression step and become squamous cell

carcinomas (SCCs). The DMBA/TPA induced multi-stage car-

cinogenesis model has been used to test many hypotheses

in cancer biology, prevention and treatment of cancer

(Abel et al., 2009).

In this study, we used 18F-FDG microPET and microCT

analyses to monitor tumor metabolism longitudinally

during tumor development induced by DMBA/TPA. We

then assessed the relationship between 18F-FDG uptake in

papillomas and the subsequent fate of the tumors, to deter-

mine if microPET analysis of papillomas can predict papil-

loma fate.

2. Materials and methods

2.1. Mice and materials

Female FVB/N mice were purchased from Charles River Labo-

ratory (Wilmington, MA). Animal experiments were carried

out with Animal Research Committee approval at UCLA.

DMBA and TPA were purchased from Sigma (St. Louis, MO).

2.2. Tumor experiments

Mice were shaved on the dorsal skin area. Two days after

shaving, they were treated topically with 100 mg of DMBA in

200 ml of acetone. One week after initiation, the mice were

treated with 2.5 mg of TPA in 200 ml acetone once a week until

the end of the experiment.

2.3. Positron emission tomography/computedtomography imaging

Positron emission tomography (PET)/computed tomography

(CT) scans were performed with a microPET FOCUS 220 PET

scanner (Siemens Preclinical Solutions, Malvern, PA) and

a MicroCAT II CT scanner (Siemens Preclinical Solutions). Re-

peated microPET and microCT images were taken before re-

peated TPA treatments. The mice were injected i.p. with

approximately 200 mCi/mouse of 18F-FDG, anesthetized with

2% isoflurane and kept, under anesthesia, at 34�C during

tracer uptake and during subsequent microPET and microCT

imaging analyses. After 1 hour uptake of 18F-FDG tracer,

microPET images were taken for 10 min, followed by micro-

CAT scans for 7 min. MicroPET images were reconstructed us-

ing a three-dimensional filtered back-projection

reconstruction algorithm and were aligned with the microCT

image using software provided by the vendor. A maximum

a posteriori reconstruction protocol was used for presentation

of images. The images were displayed and analyzed with AM-

IDE software (Loening and Gambhir, 2003). Tumor 18F-FDG up-

take was determined by a three dimensional region of interest

(ROI) analysis and normalized by the 18F-FDG uptake in the

brain (Abbey et al., 2006); consequently the 18F-FDG uptake

values reported in the Results are unitless.

2.4. Tumor grading

After mice were euthanized, tumors were harvested for histo-

logic grading. Hematoxylin-eosin stained tumor tissue sec-

tions were graded in a blinded manner by a board certified

veterinary pathologist. Tumors were graded as papilloma

(grades 1–3), microinvasive squamous cell carcinoma (grades

1–3), or fully invasive squamous cell carcinoma (Thomas-

Ahner et al., 2007) and defined as follows: papillomas are exo-

phytic tumors that show no evidence of stromal invasion.

Squamous cell carcinomas have a more endophytic appear-

ance, with stromal invasion evidenced by loss of basement

membrane continuity and development of an inflammatory

stromal response. A grade 1 papilloma is composed primarily

of epithelium without a pronounced papillary pattern. A grade

2 papilloma is a well-differentiated papillary mass. A grade 3

papilloma is similar to a grade 2 papilloma, except that

a few finger-like projections of atypical cells at the base of

the mass are present. Microinvasive squamous cell carcino-

mas are subcategorized by depth of penetration into the der-

mis. Only tumors that invaded the panniculus carnosus were

classified as fully invasive squamous cell carcinomas. All

grades of papillomas were considered premalignant. Squa-

mous cell carcinoma and all grades of microinvasive squa-

mous cell carcinoma were considered malignant.

M O L E C U L A R O N C O L O G Y 4 ( 2 0 1 0 ) 1 1 9 – 1 2 5 121

3. Results

In the DMBA/TPA induced skin cancer model conversion of

premalignant papillomas to malignant squamous cell carci-

nomas generally occurs at a low rate. However, this rate varies

among murine strains. To obtain an analyzable number of

malignant tumors FVB/N mice, which are highly susceptible

for SCC development because of a polymorphism in the

Patched gene (Hennings et al., 1993; Wakabayashi et al.,

2007), were used in this study.18F-FDG microPET/microCT imaging was performed for

eight FVB/N mice on which skin tumors were induced by

DMBA/TPA treatment. Initial photographic images and 18F-

FDG microPET/microCT images were begun between 11–14

weeks after DMBA treatment, when tumors on each mouse

can be clearly distinguished; successive images from one

mouse are shown in Figure 1. Imaging was repeated at two-

week intervals and continued up to 15–24 weeks, until total tu-

mor burden reached the maximal size permitted for the ap-

proved protocol. After the last image, mice were euthanized

and tumors were processed for histological examination

(Figure 2).

A total of 61 tumors from the eight DMBA/TPA treated mice

were analyzed for 18F-FDG uptake and histology. A three-

Figure 1 – Example longitudinal imaging of developing DMBA/TPA induce

times after DMBA treatment (lower panels). To show the signal from skin

masked. Photos were taken at the same times (upper panels). Correspondin

scale indicates uptake relative to brain, with red being the highest, and lower

the 18F-FDG concentration in brain.

dimensional ROI for each tumor was defined, based on

microCT images. The maximal uptake value in each three-

dimensional ROI was used to evaluate tumor 18F-FDG uptake.

To examine a possible correlation between 18F-FDG uptake

and tumor stage, tumor 18F-FDG uptake values at the last time

point prior to sacrifice were compared with histologic tumor

grades (Figure 3A). All fully invasive SCCs show 18F-FDG up-

take greater than 1.8; in addition, the average value for fully

invasive SCC 18F-FDG uptake is significantly higher than that

of other tumor grades (P< 0.01 by unpaired t-test).

Invasion beyond the basement membrane is the hallmark

that distinguishes malignant from premalignant tumors in

this skin tumor paradigm (Kemp, 2005; Abel et al., 2009). In

this histological view, microinvasive tumors are also consid-

ered to be malignant. However, the average 18F-FDG uptake

value for microinvasive tumors is similar to the average 18F-

FDG uptake value for premalignant papillomas rather than

to the average 18F-FDG uptake value for fully invasive SCCs

(Figure 3A); average 18F-FDG uptake values for microinvasive

tumors and papillomas are not significantly different from

one another. Moreover, premalignant papillomas and micro-

invasive tumors show great variability of 18F-FDG uptake;

some individual papillomas and microinvasive tumors have18F-FDG values within the range observed for SCCs. Thus there

is no clear 18F-FDG value that can distinguish between

d skin tumors. 18F-FDG PET/CT images were taken at the indicated

tumor in two dimensional images, signals from internal organs are

g tumors are indicated by numbered arrows in each panel. The color

values in yellow, green and blue. Signal intensities were normalized to

Figure 2 – Representative histological views of DMBA/TPA induced skin tumor types. Tumors were harvested after the last imaging time points

and processed for hematoxylin-eosin staining. (A) Papilloma, grade 1–2. (B) Papilloma, grade 3. (C) Microinvasive squamous cell carcinoma, grade 1.

(D) Microinvasive squamous cell carcinoma, grade 2. (No microinvasive squamous cell carcinomas, grade 3, were observed). (E) Fully invasive

squamous cell carcinoma.

M O L E C U L A R O N C O L O G Y 4 ( 2 0 1 0 ) 1 1 9 – 1 2 5122

premalignant and malignant tumors in the DMBA/TPA tumor-

igenesis model. Tumor 18F-FDG uptake was also compared

with 18F-FDG uptake in normal skin. Average 18F-FDG uptake

for all tumor classes is significantly higher than that of normal

skin (Figure 3A).

We also analyzed 18F-FDG uptake as a function of tumor

volume, at the last time point prior to euthanasia, for these

sixty-one tumors (Figure 3B). All fully invasive SCCs show

3

2

1

0normal

skinpap1-2

pap3

MI1

MI2 SCC

max

FD

G u

ptak

e

A B

Figure 3 – 18F-FDG uptake in each tumor shortly before mice were eutha

(A) Maximum uptake values of 18F-FDG for normal skin (without tumor) a

of each group is shown as a horizontal bar. (B) Maximum 18F-FDG uptake

grade 1–2 papillomas, pap 1–2; grade 3 papillomas, pap 3; grade 1 microinva

cell carcinomas, MI2; and fully invasive squamous cell carcinomas, SCC.

significantly greater size along with higher 18F-FDG uptake.

However, for other tumor grades, including malignant micro-

invasive tumors, there is no correlation between tumor size

and 18F-FDG uptake.

At the last time point, immediately before tumors were

evaluated histologically, all SCCs were significantly larger

than any other tumor (Figure 3B). Early growth rates for papil-

lomas destined to become SCCs were similar to the growth

pap 1-2pap 3MI 1MI 2SCC

0 200 400 600 800 1000

3

2

1

0

max

FD

G u

ptak

e

tumor size (mm3)

nized and tumors were processed for histological examination.

nd for each tumor, for various tumor histological grades. The average

values for each tumor, plotted versus tumor volume. Symbols identify

sive squamous cell carcinomas, MI1; grade 2 microinvasive squamous

10 12 14 16 18 20 22weeks

1000

800

600

400

200

0

tum

or s

ize

(mm

3 )

10 12 14 16 18 20 22weeks

3

2

1

0

max

FD

G u

ptak

e

BA

Figure 4 – (A) Estimated volume by CT of fully invasive squamous cell carcinomas (red lines) and representative papillomas (blue lines).

(B) Maximum uptake of 18F-FDG of the tumors shown in (A).

M O L E C U L A R O N C O L O G Y 4 ( 2 0 1 0 ) 1 1 9 – 1 2 5 123

rates of papillomas that did not progress to SCCs (Figure 4A).

Papillomas that subsequently progressed to SCCs then dem-

onstrate a more rapid growth rate.

We utilized the advantage of longitudinal, non-invasive,

repeated microPET imaging to determine whether patterns

of 18F-FDG uptake during the progression period of papillomas

that subsequently become SCCs are distinguishable from 18F-

FDG uptake patterns of papillomas that do not progress to

SCCs (Figure 4B). The transition to tumors that will become

SCCs is not correlated with a distinctive pattern of 18F-FDG up-

take during the papilloma stage; transition to a SCC commit-

ted path cannot be predicted from the pattern of 18F-FDG

uptake during the promotion or progression stages of DMBA/

TPA induced carcinogenesis (Figure 4B).

In a separate analysis of three of the tumor bearing mice

that were subjected to six microPET/microCT scans at two

week intervals (weeks 14–24), a comparison of the slopes of

the normalized maximum %ID/g of tumors that remained as

papillomas (grades 1–3, PAP1-3) versus the normalized maxi-

mum %ID/g of papillomas destined to become either microin-

vasive squamous cell carcinomas (grades 1 and 2) or fully

invasive squamous cell carcinomas (normalized to muscle,

MI/SCC) was performed, to see if this alternative analysis in

10 12 14 16 18 20 22weeks

0

160

120

80

40tum

or s

ize

(mm

3 )

BA

Figure 5 – Comparison of tumor volume (A) and maximum

mice where tumor burden permitted a greater number of im-

aging sessions could distinguish between tumors that

remained as premalignant papillomas and tumors that pro-

gressed to carcinomas. This analysis also failed to distinguish

tumors that were classified as PAP1-3 premalignant tumors at

the conclusion of the experiment from those that had pro-

gressed to MI/SCC (P> 0.05; data not shown). Linear discrimi-

nant analysis was also not able to distinguish between

papillomas destined to become malignant MI/SCC tumors

and papillomas that did not progress; correct classification ac-

curacy was only about 60% (cross validated; 56%), depending

on the choices of predictor variables.

In this tumorigenesis model papillomas either progress to

malignant SCCs, remain as premalignant tumors, or regress

in size. To evaluate whether the 18F-FDG uptake predicts

and/or correlates with reduction in tumor size, we once again

utilized the advantage of non-invasive, longitudinal, repeated

microPET imaging to monitor 18F-FDG uptake in papillomas

that decreased in size, and compared FDG uptake with size

change (Figure 5). There is no characteristic change of 18F-

FDG uptake before tumors regress in size.

Finally, we investigated whether 18F-FDG uptake is sensi-

tive enough to indicate the location of an emerging tumor

10 12 14 16 18 20 22weeks

0

1.6

1.2

0.8

0.4max

FD

G u

ptak

e

uptake of 18F-FDG (B) in regressing tumors in size.

–1 0 +10

Weeks

FDG

upt

ake

0.2

0.4

0.6

0.8

*

Figure 6 – 18F-FDG uptake in emerging tumors. Maximum 18F-FDG

uptake was determined on ROIs placed over the tumor area using the

CT image as reference, one week before (week L1) and after (week

D1) the tumor was initially clearly defined on the CT scan (week 0).

Data are normalized to brain 18F-FDG uptake and are expressed as

means ± s.d. (n [ 6). * P < 0.05, one-way ANOVA followed by

Bonferroni test.

M O L E C U L A R O N C O L O G Y 4 ( 2 0 1 0 ) 1 1 9 – 1 2 5124

before the tumor is morphologically detectable. To answer

this question, the 18F-FDG uptake values for 6 tumors (on

two mice) were compared at one week prior to and one

week after the tumors were clearly defined by CT scan

(1 mm diameter). 18F-FDG uptake values observed when the

tumors are first clearly distinguishable by microCT analysis

(week ‘‘0’’ in Figure 6) are not significantly different from the

values observed at the same sites one week earlier. In the

DMBA/TPA skin tumor model 18F-FDG uptake is not able to

predict the emergence of a tumor prior to morphological/

structural appearance of the tumor.

4. Discussion

Many tumors, in contrast to their normal cells of origin, use

aerobic glycolysis (the Warburg effect) and have elevated rates

of glucose uptake (Vander Heiden et al., 2009). Consequently,

imaging of tumor glucose metabolism with 18F-FDG PET can,

in many cases, differentiate malignant tissue from benign le-

sions in human patients (Phelps, 2000). The use of microPET,

an imaging system developed for small animals, provides an

opportunity to analyze tumor glucose metabolism in murine

disease models (Herschman, 2003).

Tumorigenesis is a multistep process that involves a se-

ries of genetic and epigenetic alterations, e.g., dominant on-

cogene activation and tumor-suppressor gene inactivation.

The accumulated mutations change the behavior of cells

from normal growth control to unrestricted growth, leading

to malignancy, invasion into surrounding tissues, and me-

tastasis. The DMBA/TPA mouse skin carcinogenesis model

establishes links between genetic and biochemical pathways

of initiation, promotion and progression with histological

stages of tumor development (Kemp, 2005). Histology is

the gold standard for assessing the malignancy status of

these tumors. In this study, we assessed 18F-FDG uptake in

the DMBA/TPA induced mouse skin carcinogenesis model.

We find that elevated 18F-FDG uptake, detectable by micro-

PET analysis, is present in all tumors when papillomas are

morphologically identifiable. However, by analyzing the re-

lationship between tumor malignancy and 18F-FDG uptake,

we find that 18F-FDG uptake is not correlated with tumor

malignancy; no clearly distinguishable threshold 18F-FDG

value or pattern of 18F-FDG uptake in tumors progressing

to malignancy can distinguish premalignant from malignant

tumors.

In DMBA/TPA carcinogenesis, repeated TPA treatment

causes skin hyperplasia. These hyperplastic, but preneo-

plastic, lesions do not exhibit substantially elevated18F-FDG uptake. In contrast, significantly elevated 18F-FDG

uptake is observed in all tumors; premalignant papillomas

can be clearly distinguished from normal skin and from

preneoplastic regions. DMBA/TPA skin tumor induction is

nearly always initiated by an oncogenic H-ras mutation

(Quintanilla et al., 1986). The initiated cell, with an H-ras

mutation, is ‘‘promoted’’ by repeated TPA treatment to ex-

pand into a papilloma. Ras activation is implicated in regu-

lation of aerobic glycolysis (Gillies et al., 2008). For example,

oncogenic H-ras stimulates glycolysis and inhibits oxygen

consumption in rat embryo cells (Biaglow et al., 1997) and

inhibition of H-ras resulted in diminished glycolysis and

cell death in glioblastoma cells (Blum et al., 2005). Our

data suggest that activating mutations in H-ras could con-

tribute to the higher 18F-FDG uptake we observe in all pap-

illomas. However, elevated 18F-FDG uptake is not detected

before tumors are identified morphologically by microCT,

although cells with activated H-ras genes must be present.

Our inability to detect these cells may be due to the finite

spatial resolution of microPET imaging; the ability to detect

affected tissues whose volumes are substantially smaller

than the size corresponding to the imaging spatial resolu-

tion may limit the sensitivity of the microPET assay. Alter-

natively, additional biological events could be required for

elevated 18F-FDG uptake after tumors are visible.

In SCCs, loss of heterozygosity and/or mutation of the p53

gene occurs frequently (Kemp, 2005). Wild-type p53 plays

a key role in regulating glycolysis and glucose consumption

(Kondoh et al., 2005; Bensaad and Vousden, 2007). All fully inva-

sive SCCs in this study show elevated 18F-FDG. However, vari-

able and, in some cases, high 18F-FDG uptake – as great as

that observed in SCCs – is also observed in some papillomas.

It is unlikely that these papillomas, which did not progress to

SCCs, would have p53 mutations. This complex pattern of ele-

vated 18F-FDG uptake in papillomas, microinvasive SCCs and

fully invasive SCCs in the DMBA/TPA skin multistep tumori-

genesis model is consistent with the view that ‘‘the altered ex-

pression of classical cancer-related genes cannot be the only

explanation for the development and maintenance of the aber-

rant glycolytic phenotype of cancer cells’’ (Ortega et al., 2009).

The relationship between 18F-FDG uptake and tumor grade

may differ for cancers of differing origins and types. In human

tumors, a relatively strong correlation was reported in gliomas

and sarcomas, however several benign or borderline malig-

nant tumors demonstrated intense 18F-FDG uptake (Buerkle

and Weber, 2008). Increased 18F-FDG uptake before transition

M O L E C U L A R O N C O L O G Y 4 ( 2 0 1 0 ) 1 1 9 – 1 2 5 125

to an invasive phenotype also occurs in a mouse syngeneic

mammary tumor engraftment model (Abbey et al., 2004).

Although DMBA/TPA induced papillomas may progress to

invasive malignant carcinomas, most papillomas follow dif-

ferent fates. Some papillomas grow without progression to

malignancy. Other papillomas stay the same size, while still

other papillomas regress in size. Because alterations in glu-

cose metabolism might precede and predict alterations in tu-

mor cell proliferation, we analyzed longitudinal 18F-FDG

uptake in papillomas that regressed in size. However, prior18F-FDG uptake is unable to predict subsequent reduction in

papilloma size; 18F-FDG uptake during early tumor prolifera-

tion is not a good surrogate marker to predict the fate of pap-

illomas in DMBA/TPA skin tumorigenesis.

In conclusion, elevated 18F-FDG uptake is observed in all

DMBA-TPA induced skin tumors, when they are identifiable

morphologically by eye or by microCT, but not before. Although18F-FDG uptake is high in all malignant fully invasive SCCs, the

level of 18F-FDG uptake in individual pre-malignant papillomas

is not informative with regard to their subsequent fate.

Acknowledgements

We thank Arthur Catapang and the members of the UCLA Small

Animal Imaging Shared Resource for technical assistance.

These studies were supported by NIH awards R01 CA084572,

R01 CA 123055 and P50 CA086306 to HRH, and CA100140 to SF.

IPK was supported by an overseas associateship from the De-

partment of Biotechnology, Government of India.

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