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Hypoxia Triggers the Intravasation of Clustered Circulating Tumor Cells.

ABSTRACT: Circulating tumor cells (CTCs) are shed from solid cancers in the form of single or clustered cells, and the latter display an extraordinary ability to initiate metastasis. Yet, the biological phenomena that trigger the shedding of CTC clusters from a primary cancerous lesion are poorly understood. Here, when dynamically labeling breast cancer cells along cancer progression, we observe that the majority of CTC clusters are undergoing hypoxia, while single CTCs are largely normoxic. Strikingly, we find that vascular endothelial growth factor (VEGF) targeting leads to primary tumor shrinkage, but it increases intra-tumor hypoxia, resulting in a higher CTC cluster shedding rate and metastasis formation. Conversely, pro-angiogenic treatment increases primary tumor size, yet it dramatically suppresses the formation of CTC clusters and metastasis. Thus, intra-tumor hypoxia leads to the formation of clustered CTCs with high metastatic ability, and a pro-angiogenic therapy suppresses metastasis formation through prevention of CTC cluster generation.

SUBMITTER: Donato C

PROVIDER: S-EPMC7487783 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Hypoxia Triggers the Intravasation of Clustered Circulating Tumor Cells

Project description:Circulating tumor cells (CTCs) are shed from solid cancers in the form of single or clustered cells, with the latter displaying an extraordinary ability to initiate metastasis. Yet, the biological phenomena that trigger the intravasation of CTC clusters are largely unknown. Here, we compare gene expression of hypoxic and normoxic CTC clusters to identify genes that are not only upregulated as a consequence to hypoxia, but that may also play a pivotal role in promoting CTC clusters generation and metastasis.

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Hypoxia Triggers the Intravasation of Clustered Circulating Tumor Cells

Project description:Hypoxia Triggers the Intravasation of Clustered Circulating Tumor Cells

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Project description:Metastasis, a process that requires tumor cell dissemination followed by tumor growth, is the primary cause of death in cancer patients. An essential step of tumor cell dissemination is intravasation, a process by which tumor cells cross the blood vessel endothelium and disseminate to distant sites. Studying this process is of utmost importance given that intravasation in the primary tumor, as well as the secondary and tertiary metastases, is the key step in the systemic spread of tumor cells, and that this process continues even after removal of the primary tumor. High-resolution intravital imaging of the tumor microenvironment of breast carcinoma has revealed that tumor cell intravasation exclusively occurs at doorways, termed "Tumor MicroEnvironment of Metastasis" (TMEM), composed of three different cell types: a Tie2high/VEGFhigh perivascular macrophage, a Mena overexpressing tumor cell, and an endothelial cell, all in direct contact. In this review article, we discuss the interactions between these cell types, the subsequent signaling events which lead to tumor cell intravasation, and the role of invadopodia in supporting tumor cell invasion and dissemination. We end our review by discussing how the knowledge acquired from the use of intravital imaging is now leading to new clinical trials targeting tumor cell dissemination and preventing metastatic progression.

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