Ecological paradigms to understand the dynamics of metastasis

Abstract

The process by which prostate cancer cells non-randomly disseminate to the bone to form lethal metastases remains unknown. Metastasis is the ultimate consequence of the long-range dispersal of a cancer cell from the primary tumor to a distant secondary site. In order to metastasize, the actively emigrating cell must move. Movement ecology describes an individual's migration between habitats without the requirement of conscious decision-making. Specifically, this paradigm describes four interacting components that influence the dynamic process of metastasis: (1) the microenvironmental pressures exerted on the cancer cell, (2) how the individual cell reacts to these external pressures, (3) the phenotypic switch of a cell to gain the physical traits required for movement, and (4) the ability of the cancer cell to navigate to a specific site. A deeper understanding of each of these components will lead to the development of novel therapeutics targeted to interrupt previously unidentified steps of metastasis.

Keywords: Dispersal; Epithelial–mesenchymal-transition; Homing; Metastasis; Microenvironment; Transmogrification.

Figure 1. Movement paradigm for metastatic prostate cancer

A general paradigm to describe the dynamic interactions of four critical factors that contribute to cancer cell metastasis. In green, the external factors encompass all of the influences within the ecosystem of the primary microenvironment, including other cells and abiotic factors, that influence an individual cell movement. In purple are the interrelated factors of the individual cancer cell. Intrinsic reaction describes the cell’s altered movement goals based on the pressures of external factors. Movement ability is the biomechanical requirements for locomotion. Directional navigation is the ability of the cell for site-directed movement. All of these factors interact to influence Dispersal, in orange, ultimately resulting in metastasis.

Figure 2. The epigenetic transmogrification between morphs

The (A) stay-at-home morph grasshopper and (B) dispersing locust morph share the same genetic background. (Adapted from a photograph courtesy of Compton Tucker, NASA.) The prostate cancer cell line PC3 was induced to undergo an epithelial-to-mesenchymal transition, resulting in two distinct stable cell lines, phenotypically epithelial PC3-epi (C) and mesenchymal PC3-emt (D) that share an identical genetic background. (Phase contrast images of cells plated on polyacrylamide gel. Scale bar = 50 μm. Image courtesy of Steven An, Johns Hopkins University.)

Figure 3. The circulatory path between the primary tumor and the bone metastatic site

Oxygenated blood exits the heart through the arterial system (red arrows) to deliver oxygenated blood to the organs. Deoxygenated blood returns to the heart through the venous system (blue arrows) where it circulates through the lungs to become oxygenated and repeat the circuit.

Figure 4. Transmogrification of an epithelial cell to a mesenchymal cell

Transmogrification resulting in phenotypically distinct morphs in ecology occurs both as result of a highly plastic individual transformation and as result of a developmental epigenetic trigger in an organism’s offspring. It is unclear whether the epithelial-to-mesenchymal transition occurs in a single cell with a highly plastic phenotype (individual transmogrification) or if a cell division is required for the mesenchymal morph to arise (generational transmogrification).

Figure 5. Tumor cells clustered with white blood cells in a patient with prostate cancer

Prostate cancer cells (Cytokeratin+/androgen receptor+) are clustered with white blood cells (CD45+) in a bone marrow aspirate from a patient with metastatic castrate resistant prostate cancer. (Immunofluorescence microscopy image 40X; blue = 4’,6-diamidino-2-phenylindole [DAPI] nuclear stain; red = cytokeratin; green = CD45; white = androgen receptor. Image courtesy of Peter Kuhn and Anders Carlsson, University of Southern California.)