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Metastatic Dormancy Imposed by the Primary Tumor: Does it Exist in Humans?

¹ Department of Pathology, University Medical Centre Nijmegen, PO Box 9101, Nijmegen, The Netherlands
² Department of Surgical Oncology, University Medical Centre Nijmegen, PO Box 9101, Nijmegen, The Netherlands
³ Department of Surgery, The Netherlands Cancer Institute, Amsterdam, The Netherlands

Correspondence: Address correspondence and reprint requests to: Charlotte F. J. M. Peeters, PhD, MD; E-mail: c.peeters{at}chir.umcn.nl

Background: In cancer patients, occult micrometastases may become apparent shortly after removal of the primary tumor. Animal experiments have shown that metastatic dormancy is maintained by apoptosis, and that primary tumor removal induces a flare-up of angiogenesis, leading to metastatic outgrowth. This phenomenon has led to the hypothesis that the primary tumor generates certain factors that inhibit angiogenesis at distant sites. It is still unknown whether such a phenomenon is operative in human cancer as well. Should it occur, it might have important therapeutic consequences.

Materials and Methods: Evidence for such a mechanism may be obtained from studies that analyze a series of tissue samples of metastases, taken before or after surgical removal of the primary lesion.

Results: Data from our laboratory on colorectal cancer have shown that, in the absence of the primary tumor, vascular density in the metastases is increased as well as their metabolic activity, as measured by ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography (PET). Mitotic activity is increased mildly, while levels of apoptosis are collapsed.

Conclusion: These data indicate that a mechanism of primary-tumor-induced inhibition of angiogenesis exists, maintaining metastatic dormancy. We now suggest that this mechanism may be exploited to avoid the use of exogenous, potentially harmful angiogenesis inhibitors such as bevacizumab in a neoadjuvant setting. Treatment of patients with the primary tumor still in situ could thus be restricted to chemotherapy, since the synergistic effect of an angiogenesis inhibitor would be generated by the primary tumor itself. In the present paper the clinical relevance and possible consequences of our findings and suggestions are discussed.

Key Words: Angiogenesis • Colorectal cancer • Liver metastases