Gastrointestinal
Liver Regeneration Stimulates Tumor Metastases

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Background

Partial hepatectomy for patients with colorectal liver metastases is associated with a tumor recurrence rate approaching 80% post-resection. Different factors and phases associated with regeneration of the liver are implicated in tumor recurrence. This study investigates the effects of the early and late phases of liver regeneration and the impact of the degree of liver resection on stimulating tumor growth and metastasis.

Materials and methods

Groups of mice underwent partial hepatectomy (37% or 70%) and were then challenged with colorectal liver carcinoma (CRC) tumors immediately after liver resection (early and late phase effect) or 6 days post liver resection (late phase effect). Tumor growth, degree of proliferation, tumor morphology, and the presence of extrahepatic metastases were investigated 21 days post-tumor induction.

Results

The late phase of liver regeneration plays a significant role in tumor stimulation and metastasis. The degree of hepatectomy also appears to be an important factor. The degree of hepatic resection significantly influences tumor growth and the extent of extrahepatic metastases, particularly in the lungs.

Conclusions

Elucidation of the processes involved in the late phase of liver regeneration may assist in the development and timing of adjuvant agents to minimize tumor recurrence during this phase.

Introduction

In Australia, colorectal cancer is the most common cancer across both genders. Approximately one in 26 women and one in 17 men will ultimately develop colorectal cancer during their lifetime [1]. At least 50% of patients diagnosed with colorectal cancer (CRC) will develop liver metastases, which is the major cause of mortality. At present, hepatic resection is the preferred option for selected patients with localized CRC liver metastases. Partial hepatectomy for metastases however, is associated with a 60 to 80% tumor recurrence rate [2]. This recurrence has been linked to several factors, including the accuracy of staging techniques and positive resection margins. A further factor involved may be liver regeneration following hepatic resection, which may stimulate occult tumor growth at both intra-hepatic and extra-hepatic sites.

The process of liver regeneration occurs in two major stages. The early stage is characterized by an up-regulation of numerous factors involved in the restoration of hepatic mass. The late phase involves the regulation of factors concerned with the re-establishment of liver structure. Irrespective of the extent of liver that is surgically resected, liver regeneration occurs over the same period of time. The concentration levels of the factors of both the early and late phase are modulated by the regeneration signal to achieve liver mass replacement within the time frame [3]. Many of the factors up-regulated in liver regeneration have also been implicated in tumor growth and recurrence [4, 5, 6] and the extent of their up-regulation may depend on the degree of liver resection.

This study examines the effects of early and late phases of liver regeneration on the growth of colorectal cancer liver metastases in an established mouse model, after minor (37%) and major (70%) hepatic resection.

Section snippets

Animals

Male CBA mice (8–10 weeks old) acquired from Adelaide University animal facility, South Australia were used according to Austin Health Animal Ethics Committee approval.

Maintenance of Colon Cancer Cell Line

Primary colon cancer cells were obtained from a mouse colorectal (MoCR) cell line derived from a dimethylhydrazine (DMH) induced primary colon carcinoma in CBA mice [7]. This cell line is specific to CBA mice and has been used for the characterization of the intrasplenic induction model that has been used in our department since

Quantitative Stereology of Liver Metastases

When tumors were induced immediately following resection (study A), there was no evidence of tumor stimulation in either the 37% or 70% resection groups. As seen in Fig. 1A the percentage of liver metastases ([tumor volume/total liver volume] ×100) in the 37% and 70% resection groups was not significantly different to control (P = 0.463, Tukey HSD). In study B, however, where liver metastases were induced on day 6 following 37% or 70% resection, there was a significant increase in tumor growth

Discussion

Surgical resection for CRC liver metastases is the preferred option for selected patients with colorectal cancer liver metastases, with a 5-year survival approaching 30 to 40% [10, 11, 12, 13]. Tumor recurrence occurs in 60 to 80% of patients following liver resection. This recurrence may arise in both the remnant liver as well as at extrahepatic sites [14].

Tumor recurrence after partial hepatectomy may be a result of various factors. Limitations exist in the staging techniques before surgery.

Acknowledgments

We would like to thank Theodora Fifis and Cathy Malcontenti-Wilson of the Department of Surgery, Austin Hospital, Victoria, Australia, for their help with revising this manuscript.

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