Do metastatic tumours from an unknown primary reflect angiogenic incompetence of the tumour at the primary site?—a hypothesis

Metastases from unknown primary tumours (MUP) are not an uncommon clinical problem. A hypothesis that discusses the plausible role of neoangiogenesis, as a central theme in the development of MUPs, is presented. Invasive cancers, which cannot or do not switch to the angiogenic phenotype, remain subclinical. In situations where a non-angiogenic tumour attempts to grow beyond the volume that can be supported by the vasculature, marked apoptosis and cell turnover result. Tumours with a high cell turnover are biologically advanced. Thus, such subclinical tumours acquire a metastatic phenotype. In the viscera, metastases may remain dormant for varying periods until subclones with an angiogenic phenotype arise due to tumour evolution or they burn out. Visceral MUPs, due to their longer evolution, are biologically advanced and have dismal prognosis. Contrary to this, tumour cells reaching lymph nodes (LN) grow without acquiring any phenotypic or genotypic change, as angiogenesis is redundant for growth within the metastatic LNs.