Distinct contributions of angiogenesis and vascular co-option during the initiation of primary microtumors and micrometastases

Abstract

Primary tumors and metastases have been thought to initiate avascularly as multicellular aggregates and later induce angiogenesis or initiate vascularly by co-opting pre-existing host blood vessels without inducing angiogenesis. These two distinct concepts of microtumor vascularization have raised significant controversies. To clarify intratumoral vascularization and tumor cell behaviors at single-cell level during the earliest stage of microtumor initiation, we established primary and metastatic microtumor models in Tg(flk1:EGFP) transgenic zebrafish. We found that tumor cells preferred to initiate avascularly as multicellular aggregates and only later (50-100 cells in size) induced angiogenesis in blood-supply-sufficient microenvironments. In blood-supply-deficient microenvironments, less tumor cells (20-30 cells per fish) managed to co-opt and migrate along host vessels, whereas more tumor cells (100-300 cells per fish) could immediately induce angiogenesis without obvious cell migration. In a metastatic model, we clearly observed that tumor cells co-opted, migrated along and proliferated on the surface of host vessels at an early stage after they extravasated from host vessels and induced angiogenesis later when micromatastases comprised only 15-30 tumor cells. Moreover, the inducement of neovessels accelerated the growth of micromatastases in size, meanwhile, decreased the migration of tumor cells on the surface of host vessels. These results suggest that vessel co-option and angiogenesis have distinct contributions during the initiation of microtumors. Microtumors initiated reasonably through co-opting host vessels or inducing angiogenesis, depending on the differences of local microenvironments and cell numbers in microtumors. The results in this study may have important implications for the therapeutic application of antiangiogenic strategies.

Roles of long noncoding RNAs in colorectal cancer metastasis

“…However, the association between angiogenesis and lncRNAs in CRC are still not reported yet. Recently, more evidences indicated that angiogenesis may not be necessary for carcinoma metastases [158, 159], whereas co-opting host vessels is the essential choice for tumor cells survive [160]. Surprisingly, vessel co-option may respond for approximately 40% metastases in mCRC [161].…”

Tumor angiogenesis is caused by single melanoma cells in a reactive oxygen species and NF-κB dependent manner

“…This hypothesis is supported by results from injections of melanoma cells of different malignancy into flk1::egfp-transgenic zebrafish embryos. 100-300 non-metastatic B16 mouse melanoma cells were necessary to induce angiogenesis, whereas the metastatic melanoma cell line B16-F10 required only 15-30 cells to induce an angiogenic response (Zhao et al, 2011). The angiogenesis-inducing capacity of melanoma cells thus seems to depend on their ability to initiate and maintain a pro-angiogenic signaling threshold.…”

Tumor Blood Vessels and Vasculogenic Mimicry – Current Knowledge and Searching for New Cellular/Molecular Targets of Anti-Angiogenic Therapy

“…According to the results of Zhao and co-workers [95], co-option is a strategy providing survive of tumor in difficult conditions. This process is only seemingly more favourable than sprouting angiogenesis.…”

“…From the results on Danio rerio, it was found that when tumor is composed of about 20-30 cells, a co-option is observed, without angiogenesis induction. However, when the amount of tumor cells is 200-300, almost immediately sprouting angiogenesis begins [95].…”