Communication in the Cancer Microenvironment as a Target for Therapeutic Interventions

Abstract

The tumor microenvironment (TME) is a complex system composed of multiple cells, such as non-cancerous fibroblasts, adipocytes, immune and vascular cells, as well as signal molecules and mediators. Tumor cells recruit and reprogram other cells to produce factors that maintain tumor growth. Communication between cancerous and surrounding cells is a two-way process and engages a diverse range of mechanisms that, in consequence, can lead to rapid proliferation, metastasis, and drug resistance, or can serve as a tumors-suppressor, e.g., through tumor-immune cell interaction. Cross-talk within the cancer microenvironment can be direct by cell-to-cell contact via adhesion molecules, electrical coupling, and passage through gap junctions, or indirect through classical paracrine signaling by cytokines, growth factors, and extracellular vesicles. Therapeutic approaches for modulation of cell-cell communication may be a promising strategy to combat tumors. In particular, integrative approaches targeting tumor communication in combination with conventional chemotherapy seem reasonable. Currently, special attention is paid to suppressing the formation of open-ended channels as well as blocking exosome production or ablating their cargos. However, many aspects of cell-to-cell communication have yet to be clarified, and, in particular, more work is needed in regard to mechanisms of bidirectional signal transfer. Finally, it seems that some interactions in TEM can be not only cancer-specific, but also patient-specific, and their recognition would help to predict patient response to therapy.

Keywords: communication in cancer; oncology therapy; therapeutic target; tumor microenvironment.

Figure 1

The schematic visualization of direct communication in the tumor microenvironment. The sharing of information between cancer and stromal cells, such as non-cancerous epithelial cells, cancer-associated fibroblasts, immune cells, and others, can occur in different ways, e.g., via gap junction, open-ended cytoplasmic channels (tunnel nanotubes), or through direct ligand–receptor signaling and cell adhesion [18]. These dynamic interplays effectively enable the exchange of cellular cargos over short or long (tunnel nanotubes) distances. For instance, via tunnel nanotubes, mitochondria can be donated from one cell to another in two directions. Gap junctions joint the same and different types of cells and consist of connexions that include six connexins. They are able to transfer rather small molecules and metabolites [19]. Similarly, physical cell–cell attachments via adhesion proteins are impermeable for macromolecules.

Figure 2

The schematic visualization of indirect communication in the tumor microenvironment. The sharing of information between cancer and stromal cells, such as non-cancerous epithelial cells, cancer-associated fibroblasts, immune cells, and others, can occur in different ways, e.g., via extracellular vesicles or through signaling by cytokines, chemokines, and growth factors as well as metabolites-mediated communication. Exosomes can transfer many bioactive molecules over long and very long distances. Secreted signaling molecules can also travel to remote cells.

Figure 3

New therapeutic actions targeted at direct communication in the cancer microenvironment. Two ways of therapeutic options are being considered: the first is focused on attenuation or inhibition of cell–cell interaction (red lines), and the second is based on its intensification (blue arrows). ATRA—all-trans retinoic acid; Cx—connexin; TMs—tumor microtubes; TNT—tunnel nanotube.

Figure 4

New therapeutic actions targeted at indirect communication in the cancer microenvironment. Two ways of therapeutic options are being considered: the first is focused on attenuation or inhibition of cell–cell interaction (red lines), and the second is based on its intensification for efficient delivery of the drug to tumor cells (blue arrows). ACKR—atypical chemokine receptor; iExosomes—exosomes derived from mesenchymal stromal cells with KrasG12D siRNA; FASN—fatty acid synthase; mPGES-1—microsomal prostaglandin E synthase-1; SphK2—sphingosine kinase 2; SREBP—sterol regulatory element-binding protein; TCA—tricarboxylic acid cycle.