Ways of escape: are all tumours angiogenic?

The essential role of new vessel formation in neoplasia has been increasingly recognized for both primary tumour growth and for metastatic spread. Metastases are believed to be dependent on angiogenesis at two stages: ®rst, the neoplastic cells require the presence of intratumoral vessels to gain access to the circulation; and second, they need neovascularization in their target organ for their establishment. Indeed the question has been raised whether neo-angiogenesis is the unifying concept in cancer and the essential element for its clinical consequences. We believe that exceptions to this rule occur. We have proposed the hypothesis that if a tumour can obtain an ef®cient blood supply from a pre-existing suitable vascular bed that already exists then it could grow without need for the production of new vessels. If true, this has important implications with regards to anti-angiogenic therapy and the mechanisms of metastasis. Our hypothesis follows an observation we made investigating vascularization in a large series of nonsmall cell lung carcinomas. We found that immunostaining of endothelial cells highlights four distinct patterns of vascularization. Three patterns (termed basal, papillary and diffuse) have in common the destruction of normal lung architecture, the production of tumour-associated stroma and of new vessels. In the fourth pattern, that we called alveolar or non-angiogenic (observed in approximately 15% of cases) the immunostaining for the endothelial marker CD31 highlights the alveolar vessels, entrapped by the neoplastic cells ®lling the alveolar spaces. A clinicopathological study has shown that patients with a putative non-angiogenic carcinoma have more aggressive disease. Such a ®nding is not limited to primary carcinomas because we have also noted that primary angiogenic breast carcinomas can relapse as putative non-angiogenic lung metastases. These conclusions are based only on morphological observations without taking into consideration the angiogenic status of the neoplastic cells or the phenotype of intratumour vessels. Recent data from our laboratory (manuscript submitted) show that a difference exists between angiogenic and non-angiogenic tumours as far as the intratumoral vascular phenotype is concerned. We have investigated the intratumoral vessels in a series of lung carcinomas looking at the expression of LH39, a laminin epitope expressed in the basal membrane of mature vessels and aVb3, an integrin expressed on the endothelium of newly formed vessels. We found that in typical angiogenic carcinomas most of the vessels do not express LH39 but strongly express aVb3. In contrast, the intratumoral vessels in non-angiogenic tumours have the same phenotype as normal lung vessels, i.e. LH39-positive and aVb3 weak or absent. We concluded that the phenotype of intratumoral vessels in non-angiogenic tumours is consistent with that of pre-existent rather than newly-formed vessels. Furthermore, these data show that within the angiogenic tumours the phenotype of the vessels is heterogeneous, suggesting that different angiogenic pathways are activated. Recently in a rat model there has been con®rmation that tumours implanted in the brain can start to grow and become greater than 2 mm by exploiting the preexisting vessels. Only at a more advanced stage does neo-angiogenesis occur. This observation suggests that in the brain as well a signi®cant non-angiogenic neoplastic growth does occur. Can tumours grow by exploiting existing vessels in other organs? The question is rather important as the number of clinical trials with anti-angiogenic drugs keeps increasing. Such tumours would almost certainly not be blocked by this class of drugs. Four papers looking at the microvessel density in the primary tumour and in synchronous nodal metastases suggest that lymph node is another site in which tumours grow independently of their angiogenic ability. Some minor differences were present in the design of these studies. Three papers were on breast cancer and one on head and neck; three counted the microvessels in hot spots and one on the edge of the tumour; three groups used anti-Factor VIII antibody