Figure 3

Microenvironment in the metastasis process. Metastasis is a complicated multistep process that requires cancer cells to escape from the primary tumor, survive in the circulation, seed at distant sites and grow. Each step involves stromal cell and paracrine interactions of the microenvironment. Aberrantly secreted chemokines and cytokines from the primary tumor circulate into the blood stream, creating a premetastatic niche even before tumor cell mobilization. Secreted factors functionally activate bone marrow-derived cells, which are then released into the circulation to subsequently incorporate these cells into distant organs, such as lung and liver, to create a favorable microenvironment for the cancer cell to be seeded. For the cancer cells to invade into the blood circulation, proteases are produced by bone marrow-derived cells, including macrophages and fibroblasts. Following tumor cell intravasation, a series of steps is required for the establishment of secondary tumors in the metastatic sites. Disseminated cancer cells preferentially form metastases at sites where activated bone marrow-derived cells are localized and the primary tumor has created a favorable environment at the local organ. After seeding, persistent growth of the metastatic tumor requires the establishment of a vasculature that can be possibly achieved through the production of angiogenic growth factors.