Vascular development in mouse lung metastases

Dissemination of cancer cells is strongly associated with reduction in quality of life, worsening of prognosis, and remains the primary cause of therapeutic failure and high mortality in cancer. A crucial factor in the progression of metastases is the ability to establish a functioning blood vessel network. Consequently therapeutic strategies which selectively target tumor vasculature may hold promise for the treatment of metastatic disease. A complicating factor in the assessment of the efficacy of vascular targeting therapies is that the metastatic process can result in multiple neoplastic lesions at various stages of growth and vascularity in a single organ. The goal of this project was to utilize a rodent squamous cell carcinoma (SCCVII) model to characterize the development of metastatic lung lesions and their associated vasculature. Mice were injected with tumor cells via the tail vein to introduce a reproducible number of lung metastases. At various times after cell injection, lungs were removed and serial sections were taken throughout the lobes for morphometric analysis. Tumor volumes were calculated for each nodule using 2 hematoxylin and eosin (H&E) stained sections that were a known distance apart. Sections adjacent to those used for size determination were reserved for immunohistochemical staining with CD31 to identify blood vessels associated with each nodule. The results showed that although the median tumor volume increased from 0.006 to 0.51 mm(3) between 7 and 18 days post SCCVII cell injection, a range of tumor sizes existed at all-times. Irrespective of the time of assessment, nodules with volumes ≤ 0.5 mm(3) had a constant vessel density while those with volumes >0.5 mm(3) showed increasing vessel densities with increasing size. These findings indicate that the methodology outlined in this study can identify metastases in various stages of vascular development and could therefore be applied to evaluate and distinguish therapeutic interventions that seek to prevent the initiation of blood vessel networks and those targeting already established expanding tumor vasculature. Examining the efficacy of such approaches, alone or in combination, in the treatment of metastases in a preclinical model could lead to the development of more effective therapeutic strategies for metastatic disease.