Noninvasive monitoring of colonic carcinogenesis: feasibility of [18F]FDG-PET in the azoxymethane model

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Abstract

Background

Azoxymethane (AOM) is a potent carcinogen that induces colorectal cancer and adenomas in rats. [18F]FDG-PET is a molecular imaging technique that is based on the elevated uptake and retention of radiolabeled glucose. At present, it is unknown at which stage FDG accumulation occurs during the adenoma carcinoma sequence. To address this issue, we studied the FDG uptake in AOM-induced rat colorectal adenocarcinoma (CRC) and correlated this with histopathological findings.

Methods

Seventy Fischer 344 rats were injected with AOM. Terminal autopsy took place 20–38 weeks after the first AOM injection. After [18F]FDG PET scanning, the rats were sacrificed, tissue [18F]FDG uptake was measured, followed by histopathological examination.

Results

Macroscopic examination revealed 21 tumors (7 located in the small bowel and 14 in the colon) in 19 rats. On histological examination, we found 10 colonic adenocarcinomas (the first being observed at Week 22) and 7 adenocarcinoma in the small bowel. In total, seven colon adenomas were found in five rats, six of which expressed high-grade dysplasia. The [18F]FDG accumulation in small intestine carcinomas was well beyond background accumulation (P<.0001). On PET scanning, two rats showed focal accumulation of the abdominal area, corresponding to small intestine carcinomas.

Conclusion

Adenocarcinomas had a significantly higher [18F]FDG uptake than background bowel uptake. [18F]FDG uptake was lower in adenomas than in carcinomas. These data suggest that the AOM model allows the evaluation of intervention strategies with [18F]FDG uptake as a valid outcome measure.

Introduction

Colorectal adenocarcinoma (CRC) is highly prevalent and a common cause of cancer-related deaths in the Western world [1], [2]. The high disease burden has led to experimental carcinogenesis models that allow the study of the biology of cancer and the evaluation of pharmacological interventions. Azoxymethane is a potent carcinogen that induces colorectal cancers in rats and mice. The spectrum of AOM-induced epithelial lesions resembles those of the various types of neoplastic lesions in human CRC. In addition, AOM-induced CRC appears to follow the concept in which tumor initiation is followed by tumor promotion and progression in a sequential manner. Specifically, AOM induces the onset of aberrant crypt foci, as the precursor lesion, followed by the onset of adenocarcinoma most often of the distal colon, and, finally, metastasis to mesenteric lymph nodes and liver. The molecular pathogenesis is characterized by K-ras and/or beta catenin mutations. Unique to the AOM rat model is the co-occurrence of both adenomas and adenocarcinomas, and it has been estimated that 70% of colon tumors are adenocarcinomas, while the remainder are adenomas. Histologically, adenomas of the colon are noninvasive with low- to high-grade dysplasia [3].

[18F]FDG-PET is a molecular imaging technique that is based on the elevated uptake and retention of radiolabeled glucose in target tissues. The FDG uptake detected by scans allows for estimation of the cellular energy metabolism and can be used to detect stage and assess treatment of many processes, most notably malignancies [4]. FDG-PET has also been used for research purposes because it offers metabolic/functional images noninvasively, quantitatively and repeatedly, not only in humans but also in small animals. At present, it is unknown at which stage FDG accumulation occurs during the adenoma–carcinoma sequence of CRC. We reasoned that the CRC of the AOM rat model is associated with higher metabolic activity and hence increased FDG uptake. Furthermore, this model allows us to evaluate whether FDG already accumulates in adenomas. Ultimately, our goal is to develop an experimental model of metabolic imaging that visualizes the carcinogenesis of CRCs. An ideal model would allow noninvasive monitoring of the efficacy of cancer intervention/prevention strategies. To address this issue, we studied the FDG uptake in AOM-induced rat CRC and correlated this with histopathological findings.

Section snippets

Experimental model

We used the AOM rat model [5] because of the apparent similarity of the induced tumors to those occurring in humans [6]. These animals develop colonic adenomas and colon carcinomas within 5 months after AOM treatment [7]. We obtained 70 male weanling Fischer 344 rats from Charles River (Sulzfeld, Germany). Animals were kept on softwood bedding in macrolon cages, two or three per cage, under standard laboratory conditions. Rats were fed the Institute's stock diet for rats. Azoxymethane (NCI

Macroscopic examination

Macroscopic examination of small and large bowels revealed 21 tumors in 19 rats, which started to appear 22 weeks after the first AOM injection. Macroscopic inspection of the intestines demonstrated small bowel tumors in 7 animals, all located in the proximal part of the small bowel directly distal from the stomach. Fourteen tumors were located in the large bowel (n=4 distal part, n=9 mid large bowel, n=1 cecum). Two animals had more than one gastrointestinal tumor. One rat had tumors in both

Discussion

In the present study, we investigated whether [18F]FDG accumulates preferentially in (pre)malignant lesions induced by AOM in an experimental rat model. Here we show that three subcutaneous injections of AOM induced both adenomas and adenocarcinomas in the colon as well as small intestine carcinomas in F344 rats. The first adenomas appeared 22 weeks after the start of AOM injections. There was no correlation between time after AOM treatment and the appearance of gastrointestinal adenomas and

Acknowledgments

Joost P.H. Drenth is supported by a VIDI fellowship from the Netherlands Organization for Scientific Research (NWO). This work was supported in part by a Gastrostart grant from the Dutch Society of Gastroenterology. Mrs. Cathelijne Frielink is acknowledged for expert help in preparing the histological samples.

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