Epithelial and mesenchymal phenotypic switchings modulate cell motility in metastasis

Abstract

The most ominous stage of cancer progression is metastasis, or the dissemination of carcinoma cells from the primary site into distant organs. Metastases are often resistant to current extirpative therapies and even the newest biological agents cure only a small subset of patients. Therefore a greater understanding of tumor biology that integrates properties intrinsic to carcinomas with tissue environmental modulators of behavior is needed. In no aspect of tumor progression is this more evident than the acquisition of cell motility that is critical for both escape from the primary tumor and colonization. In this overview, we discuss how this behavior is modified by carcinoma cell phenotypic plasticity that is evidenced by reversible switching between epithelial and mesenchymal phenotypes. The presence or absence of intercellular adhesions mediate these switches and dictate the receptivity towards signals from the extracellular milieu. These signals, which include soluble growth factors, cytokines, and extracellular matrix embedded with matrikines and matricryptines will be discussed in depth. Finally, we will describe a new mode of discerning the balance between epithelioid and mesenchymal movement.

Figure 1

Transition from Epithelial to Mesenchymal Phenotype. EMT results in the loss of cell-cell adhesions allowing for the autocrine stimulation as the basolaterally-restricted receptors are no longer isolated from the apically-secreted motogenic cognate growth factors.

Figure 2

Key Motogenic Intracellular Signaling Pathways Emanating from Cell Surface Receptors. Shown are select receptors and the key motogenic signaling pathways. Not shown, for clarity of the schematic, are all the overlapping signals and other, less thoroughly documented pathways that have been linked to driving motility. These pathways have been demonstrated to be viable targets limiting tumor cell motility in preclinical models.

Figure 3

Matrix-Embedded and Encoded Signals Liberated by Proteolysis. Extracellular matrix is not only recognized by adhesion and other (DDR, etc) receptors but also contains predeposited soluble factors, encoded factors, and cryptic signaling elements. Proteolysis of the matrix, mainly by matrix metalloproteinase (MMP), degrade invasion inhibitors (I) and release and uncover these signals (GF – growth factors, MK – matrikines). Invadopodial-localization of such activity can be accomplished by membrane-tethered MMP. Adapted from (56).

Figure 4

CXCR3 Isoforms Modulate Motility in Opposing Directions. CXCR3A signaling mainly via Gαq subunits activates phospholipase C-β (PLC-b) to initiate calcium influx; activation of calpain 1 at the membrane shifts the adhesion regiment to a more permissive state to facilitate motility. CXCR3B, while also signaling via Gαq subunits, more strongly initiates Gαs subunits that trigger protein kinase A (PKA) to inhibit calpain 2 and prevent rear release during motility. In normal prostate epithelial cells, only CXCR3B is expressed, but in prostate carcinoma cells, both isoforms are present at roughly equivalent levels.