Elsevier

Surgery

Volume 133, Issue 5, May 2003, Pages 547-555
Surgery

Original Communications
Increased surgical stress promotes tumor metastasis*,**,

https://doi.org/10.1067/msy.2003.141Get rights and content

Abstract

Background. Although it is well-known that excessive surgical stress augments the growth of residual cancer and metastasis, whether surgical stress is increased according to the degree of surgical manipulation and can consequently lead to the enhancement of cancer metastasis has not been thoroughly examined. Moreover, the molecules associated with response for stress-enhanced metastasis have not been well-analyzed. The aim of this study was to examine whether cancer metastasis is enhanced with an increase of surgical stress with an experimental lung metastasis model and to analyze the related molecules responsible for stress-enhanced metastasis. Methods. Colon 26-L5 carcinoma cells (1.5 × 104/mouse) were injected intravenously into 6-week-old female BALB/c mice (Japan SLC, Hamamatsu, Japan). Two hours later, the mice were divided into 5 groups: untreated controls (the C group); mice given anesthesia only (the A group); mice given anesthesia and laparotomy (the AL group); mice given anesthesia, laparotomy, and appendectomy (the ALAp group); and mice given anesthesia, laparotomy, appendectomy, and left hepatic lobectomy (the ALApH group). The anesthesia procedures were the same in all groups (intraperitoneal administration of 0.8 mg/mouse sodium pentobarbital). In the AL, ALAp, and ALApH groups, a 3-cm long laparotomy was performed, and the time of the whole operation was just 5 minutes. All mice were killed 14 days after the procedures, and the number of lung metastases on the lung surface was counted manually. At the same time, BALB/c mice without tumor burden were given the same 5 kinds of surgical stress, and the messenger RNA expression of various metastasis-related molecules in the lung was measured with reverse transcriptase-polymerase chain reaction at 6, 24, and 48 hours after surgical stress. We also examined the effect of ONO-4817 (an inhibitor of matrix metalloproteinases ([MPs]) on lung metastasis in the mice with the 5 kinds of surgical stress. Results. The numbers of lung metastases on the lung surface and the messenger RNA expression of MMP-9, membrane type IBMMP, and urokinase-type plasminogen activator at 24 hours after surgery were enhanced in proportion to the degree of surgical stress. Moreover, ONO-4817 significantly inhibited lung metastasis. Conclusion. These results strongly suggest that increased surgical stress augments cancer metastasis via surgical stress-induced expression of proteinases in the target organ of metastasis. (Surgery 2003;133:547-55.)

Section snippets

Animals

Six-week-old specific-pathogen-free female BALB/c mice were purchased from Japan SLC, Hamamatsu, Japan. The mice were maintained in the Laboratory for Animal Experiments, Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, in laminar air-flow conditions with a 12-hour light/dark cycle at a temperature of 22°C to 25°C. All animals had free access to standard laboratory mouse food and water. This study was conducted in accordance with the standards outlined in the

Experiment 1: effect of the increase of surgical manipulation on surgical stress-induced enhancement of cancer metastasis

We first examined whether surgical stress is enhanced by the increase of surgical manipulation with the experimental lung metastasis model. We measured the concentration of serum interleukin-6 3 hours after the procedure to assess the degree of surgical stress in each group. As shown in Fig 1, the interleukin-6 concentration in serum increased in proportion to the degree of surgical manipulation.

. Level of serum interleukin-6 at 3 hours after surgical operation. Six-week-old female BALB/c mice

Discussion

Surgery is generally considered to be the most effective treatment for cancer. However, surgeons often observe rapid growth and spread of residual cancer shortly after the operation and surgical stress-induced worsening of the prognosis. Factors such as excessive bleeding, lengthening of the operation time, and an increase of surgical manipulation would clearly induce surgical stress. Excessive surgical stress caused by thoracotomy or laparotomy (even for 20 or 30 minutes) has previously been

Acknowledgements

We thank Ms Kazuko Hayashi for technical assistance.

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    *

    Supported by ONO Pharmaceutical Co, Ltd, Osaka, Japan.

    **

    Reprint requests: Yasunori Tsuchiya, Second Department of Surgery, Faculty of Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan.

    0039-6060/2003/$30.00 + 0

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