Models for spontaneous metastasis.

In the Introduction of a recent review entitled ‘‘Exploring a New Twist on Tumor Metastasis,’’ Yang et al. state that, to understand the complex nature of the pathogenesis of cancer metastasis, ‘‘it is important to use experimental metastasis models that can recapitulate, at least in outline, the physiologic and pathologic conditions observed in human cancer patients.’’ The authors then state that experimental models for spontaneous metastasis (using human tumor cells) in murine models rarely spread from the implanted primary tissue, and therefore, investigators have relied on the ‘‘introduction of tumor cells directly into the systemic circulation to establish metastases in distant organs’’ (1). However, adequate models for spontaneous metastases that recapitulate the clinical reality do exist. To produce spontaneous metastasis, tumor cells with metastatic potential must be implanted into orthotopic organs. Although tumor cells produce large lesions in the subcutis, the growth in an ectopic environment generally fails to produce metastasis (2). Clinically, metastases are often diagnosed months or years after the resection of a primary neoplasm (3). Although dissemination of tumor cells from the primary tumor can occur at an early stage of disease (4), growth into grossly visible distant lesions requires weeks or months in the mouse (2). The implantation of tumor cells into orthotopic tissues often yields large local tumors that can be fatal. The primary neoplasm must therefore be surgically resected to allow sufficient time for development of distant metastases and prevent the mice from succumbing to the local tumor burden. This is certainly the case for murine melanoma implanted into the skin or foot pad followed by surgical excision (5), human colon cancer implanted into the cecum followed by cecectomy (6), human renal cancer implanted into the kidney followed by nephrectomy (7), human pancreatic cancer implanted into the pancreas followed by pancreatectomy (8), etc. By definition, a model is an approximation of reality. Animal models for spontaneous metastasis were established decades ago. These models are certainly more demanding and complicated but do include all the steps in the pathogenesis of metastasis.