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Updated August 18, 2023.
Metastasis is a complex, multi-step process in which cells originating from a primary tumor spread throughout a patient's body to form secondary tumors in distant organs. Metastatic tumors cause more than 90% of cancer deaths1 and often require multiple rounds of treatment, including chemotherapy, targeted therapy, and immunotherapy to induce remission.
A secondary tumor results from cells acquiring the ability to circumvent the molecular and physical hurdles they encounter during each stage of the metastatic process. Only a few metastasized cells overcome these hurdles - most succumb to the various stresses they face during the process2.
Interactions between cancer cells, stromal fibroblasts, endothelial cells, and immune cells, and changes in tissue oxygen tension and the architecture of the extracellular matrix architecture greatly influence metastasis and, therefore, tumor progression.
The key stages in the metastatic process are proliferation, invasion, intravasation, capture by cell adhesion, extravasation, capture by physical occlusion, and, finally, secondary tumor growth.
During the epithelial-to-mesenchymal transition (EMT), epithelial cells undergo multiple changes to acquire the properties of mesenchymal cells. These mesenchymal-like cancer cells migrate and invade tissues. Normal epithelial cell tissue architecture is maintained by contact inhibition. Cancer cells overcome contact inhibition via dysregulation of cell adhesion signaling and upregulation of master regulators of EMT, such as ZEB13.
YAP/TAZ are sensors and mediators of mechanical cues instructed by the cellular microenvironment4. The rigidity of the surrounding tumor matrix may influence tumor progression. Stiffer matrices could promote nuclear localization and activation of mechanomediators, such as TWIST1 and YAP/TAZ, leading to cytoskeleton remodeling during EMT5.
When a cell has completed the EMT process, it releases gelatinase enzymes, such as MMP-2 and MMP-9, to degrade the underlying basement membrane and allow the mesenchymal cell to migrate away from the epithelial layer in which it originated6.
Intravasation is the invasion of cancer cells through the basement membrane into the blood or lymphatic vessels. An inflammatory response introduces vascular permeability during intravasation by affecting endothelial cell-cell adhesions.
Cancer cells roll through the vascular space propelled by a series of weak adhesive interactions between selectins expressed on the surface of endothelial cells and CD44, CEA, and PODXL on the surface of tumor cells7. This rolling continues until the endothelium releases soluble adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM1) and intercellular adhesion molecule-1 (ICAM1). These molecules arrest cells through an interaction with integrin-mediated cell-matrix adhesions followed by neutrophil aggregation8,9.
The next stage is extravasation, where tumor cells induce vessel remodeling to permit invasion via integrin-mediated adhesion or TWIST1-mediated migration10. Common sites of metastasis include the lungs, lymph nodes, bones, liver, and brain. The microenvironment of the new site must be permissive to allow the tumor cell to survive and proliferate11.
As a tumor expands, the existing vascular supply is insufficient to provide enough oxygen, resulting in hypoxia. To continue expansion, a tumor requires new blood vessels to provide rapidly proliferating tumor cells with an adequate supply of oxygen and metabolites. Secondary tumors produce growth factors, such as vascular endothelial growth factors (VEGFs), to promote the formation of new blood vessels from surrounding tissues via angiogenesis12.
What to expect from this poster
The poster provides an overview of metastasis from EMT to angiogenesis. We outline several critical factors influencing this process and highlight how the tumor cell environment may promote metastasis.