Illuminating breast cancer invasion: diverse roles for cell-cell interactions

Abstract

Metastasis begins when tumors invade into surrounding tissues. In breast cancer, the study of cell interactions has provided fundamental insights into this complex process. Powerful intravital and 3D organoid culture systems have emerged that enable biologists to model the complexity of cell interactions during cancer invasion in real-time. Recent studies utilizing these techniques reveal distinct mechanisms through which multiple cancer cell and stromal cell subpopulations interact, including paracrine signaling, direct cell-cell adhesion, and remodeling of the extracellular matrix. Three cell interaction mechanisms have emerged to explain how breast tumors become invasive: epithelial-mesenchymal transition, collective invasion, and the macrophage-tumor cell feedback loop. Future work is needed to distinguish whether these mechanisms are mutually exclusive or whether they cooperate to drive metastasis.

Figure 1

Three major classes of cell interactions in breast cancer invasion. (a) Breast cancer invasion arises from diverse cell interactions that fall into three major categories: soluble factor signaling, cell–cell adhesion, and ECM remodeling. These interactions often produce molecularly specific signaling consequences and more general mechanical cues. In paracrine signaling, there is diffusion of a soluble signal from one cell to another. In autocrine signaling, the soluble signal acts upon the signal-generating cell. In juxtacrine signaling, the signal is membrane immobilized and communicates with immediate neighbors. In ECM-immobilized signaling, the secreted signal becomes immobilized to ECM often with the help of extracellular binding proteins. Subsequent matrix degradation liberates the immobilized signal. (b) Cell–cell adhesion is another major category of cell interaction. Invasive breast tumors are cohesive and typically retain E-cadherin-based homotypic contacts. Heterotypic contacts can occur between phenotypically distinct cancer cells during collective invasion. In addition, heterotypic cell adhesion also occurs between cancer cells and stromal cells such as fibroblasts and macrophages. (c) The ECM undergoes significant remodeling during tumor progression and is a potent regulator of cancer cell behavior. Cells can promote remodeling in at least four ways, by increasing synthesis, alignment, and crosslinking of matrix or by facilitating its proteolysis.

Figure 2

Major mechanisms for breast cancer invasion. Three major mechanisms have been identified to explain how breast cancers invade: EMT, collective invasion, and macrophage–tumor cell interactions. In addition, for all three of these mechanisms, tumor cell-matrix interactions with collagen I provide essential chemical and physical cues for breast cancer invasion. (a) In EMT, tumor cells transition from epithelial organization to mesenchymal motility. The EMT is variably defined by a molecular EMT that includes loss of E-cadherin and gain of mesenchymal markers, and by a morphologic EMT that includes a change to mesenchymal cell motility. As depicted, EMT models generally conceptualize the molecular EMT as occuring first in this sequence. However, recent studies indicate that mesenchymal motility can occur without going through a molecular EMT. (b) In vivo, breast tumors typically invade cohesively as a multicellular unit, termed collective invasion. In breast cancer, two leader cell populations have emerged, stromal fibroblasts and invasive leader cells, which are a specialized subpopulation of breast cancer cells. Stromal fibroblasts facilitate invasion by path clearing and matrix remodeling ahead of the collective invasion front. By contrast, invasive leader cells are directly coupled by cell-adhesion to trailing cells. (c) A third major mechanism for invasion is the interaction of macrophages and tumor cells. Macrophages promote invasion of cancer cells to blood vessels and assist in their intravasation. Macrophages promote the efficient migration of cancer cells along collagen fibers via the macrophage–tumor cell feedback loop. By a second mechanism, direct cell–cell adhesion between macrophage and cancer cell promote intravasation through endothelium.

Figure 3

An integrated model of invasion and metastasis in the MMTV-PyMT model. Three different models are possible. In the first model, collective invasion promotes local invasion whereas macrophage-led invasion promotes dissemination and distant metastasis. In the second model, metastases are generated by competing pathways that involve single cell and collective cell dissemination. In the third model, collective invasion greatly accelerates the metastatic process but metastasis obligately occurs through macrophage-led invasion and dissemination.