Circulating Tumor Cells in the Parallel Invasion Model Supporting Early Metastasis
Society for Research on Biology and Treatment of Cancer (SRBTC), 1160 Vienna, Austria
Circulating tumor cells (CTCs) seem to comprise metastasis-initiating cells and their count and phenotype represent an indicator of prognosis and response to therapy in cancer patients. In the classical model of tumor dissemination, specialized cells at the invasive front undergo epithelial-mesenchymal transition (EMT) and enter peripheral tumor-coalescing blood vessels to establish metastatic lesions by extravasation of CTCs. Thus, dissemination of cancer cells occurs after prolonged tumor development and following access to neighboring blood vessels via transit through stromal tissue. However, clinical and new experimental data indicate early tumor dissemination immediately after an angiogenic switch has occurred and an intravasation of tumor cells in the tumor core region. Accordingly, CTCs may have direct access through fenestrated and irregular intratumoral vessels and, therefore, the metastasis-initiating cells become active a long time before lesions are detected clinically. This model of cancer cell intravasation is better compatible with the release of CTC clusters and apoptotic CTCs and, furthermore, spares the requirement for an elusive and complicated EMT/MET program. Similarly, the intravasation of large number of CTCs observed in metastatic disease may be alleviated by an intratumoral process instead of a stromal crossing. This early metastasis model changes the possible pathways targeted for the prevention and inhibition of metastasis and the significance of CTCs which are detected and analyzed late after the initial phase of tumor dissemination.
Keywords: Metastasis, Circulating Tumor Cells, Intravasation, Epithelial-Mesenchymal-Transition, Angiogenesis.