Targeting tumor cell motility as a strategy against invasion and metastasis

Abstract

Advances in diagnosis and treatment have rendered most solid tumors largely curable if they are diagnosed and treated before dissemination. However, once they spread beyond the initial primary location, these cancers are usually highly morbid, if not fatal. Thus, current efforts focus on both limiting initial dissemination and preventing secondary spread. There are two modes of tumor dissemination - invasion and metastasis - each leading to unique therapeutic challenges and likely to be driven by distinct mechanisms. However, these two forms of dissemination utilize some common strategies to accomplish movement from the primary tumor, establishment in an ectopic site, and survival therein. The adaptive behaviors of motile cancer cells provide an opening for therapeutic approaches if we understand the molecular, cellular, and tissue biology that underlie them. Herein, we review the signaling cascades and organ reactions that lead to dissemination, as these are non-genetic in nature, focusing on cell migration as the key to tumor progression. In this context, the cellular phenotype will also be discussed because the modes of migration are dictated by quantitative and physical aspects of the cell motility machinery.

Figure I

During mesenchymal migration the specific steps of cytoskeletal reorganiztion, lamellipodial protrusion, new forward adhesions, transcellular contractility, and rear detachment are controlled by key signaling nexi. The key integrating molecules for each process are shown, in black for those operative during both adhesion- and growth factor-driven motility, whereas those only activated during the enhanced movement promoted by growth factor receptor activation are shown in blue italics.

Figure 1

Schematic of phenotypic changes from a normal, cell-cell connected epithelium to a disseminated carcinoma. The cells downregulate their E-cadherin (solid bars) to allow for motility in a process denoted as ‘epithelial-to-mesenchymal transition’ (EMT) which allows for migration as a syncytial mass for invasion that displaces the normal parenchyma (gray cells) or as singular cells for metastasis. The survival in the distant site likely requires a reversion of the phenotype, a ‘mesenchymal-to-epithelial reverting transtion’ (MErT) to reside among ectopic tissue epithelial cells (gray cells).

Figure 2

Invading melanoma cells can passage through tight matrices either in the mesenchymal state requiring extensive matrix remodeling (left) or the amoeboid state in which the cells ‘bleb’ through tight spaces (right). The right panels in each pair are vertical views of cells extending through a pore in the membrane. From .