Targeting tumor cell motility to prevent metastasis

https://doi.org/10.1016/j.addr.2011.04.008Get rights and content

Abstract

Mortality and morbidity in patients with solid tumors invariably result from the disruption of normal biological function caused by disseminating tumor cells. Tumor cell migration is under intense investigation as the underlying cause of cancer metastasis. The need for tumor cell motility in the progression of metastasis has been established experimentally and is supported empirically by basic and clinical research implicating a large collection of migration-related genes. However, there are few clinical interventions designed to specifically target the motility of tumor cells and adjuvant therapy to specifically prevent cancer cell dissemination is severely limited.

In an attempt to define motility targets suitable for treating metastasis, we have parsed the molecular determinants of tumor cell motility into five underlying principles including cell autonomous ability, soluble communication, cell–cell adhesion, cell–matrix adhesion, and integrating these determinants of migration on molecular scaffolds. The current challenge is to implement meaningful and sustainable inhibition of metastasis by developing clinically viable disruption of molecular targets that control these fundamental capabilities.

Introduction

Metastatic disease remains the primary cause for cancer-related deaths [1]. Whether it is present at the time of diagnosis, develops during treatment, or occurs at the time of disease relapse, the dissemination of tumor cells from the primary lesion is the principle reason for the mortality and morbidity of cancer patients. Surgical resection of the primary lesion, along with cytotoxic and cytostatic systemic therapy has been relatively successful in treating benign, localized cancer and preventing its progression to metastatic disease. Metastases, however, remain difficult to treat and render the disease incurable. Paradoxically, the more effective cancer treatment is at prolonging life, the greater the risk of metastasis. To combat the risk for eventual metastasis, many patients are over-treated with the intent of preventing dissemination of their disease.

Therapies that specifically target the motility of tumor cells could significantly improve cancer treatment by removing the threat of systemic disease and decreasing the dependency on therapeutics with detrimental side-effects. For the past 5 decades the processes involved in tumor cell metastasis have been microdissected in an attempt to identify therapeutically viable targets. The central, defining process of metastatic disease is the ability of tumor cells to mobilize, invade, and cross normally non-permissive tissue barriers. This has greatly intensified the investigation into molecular mechanisms of motility and their contribution to metastasis (Fig. 1). Here, we provide an overview of these investigations and examine the potential for targeting tumor cell motility in the treatment of metastasis.

The migration of adherent cells is defined as the translocation of cells from one location to another. Detailed discussion is available from the Cell Migration Consortium on the Cell Migration Gateway (www.cellmigration.org). Typically, migration is parsed into five component processes: polarization, protrusion, adhesion, translocation of the cell body, and retraction of the rear (Fig. 2, [2], [3]). Although it is mechanistically convenient and sometimes necessary to define cell migration in this manner, the movement of cells within a living organism is highly complex, tightly regulated, and carefully coordinated. The physiology of cell migration is also very diverse. Some cell types such as activated hemopoietic cells exhibit a highly individualized “ameboid” movement with little adhesion and no matrix remodeling. Fibroblasts, and melanocytes generally migrate in a “mesenchymal” fashion as individual cells which are highly adherent and require proteolytic remodeling of the matrix. The migration of neuronal and smooth muscle cells is collective, directionally coordinated, and mechanistically integrated. Epithelial cells, the cell type from which most cancers originate, can exhibit multiple migration phenotypes. While epithelial cells are generally present as stationary, tightly interconnected sheets of cells, they can be mobilized during development, physiological homeostasis, and wound repair. Depending on their developmental differentiation, environmental stimuli, and surrounding tissue architecture, epithelial cells can migrate as collective sheets, clusters, tubular structures, or as individual cells (reviewed by Friedl and colleagues in [4], [5] and Rørth et al. in [6]). Interestingly, in patients with malignant disease, tumor cells are found as both individual cells and organized collective sheets or clusters, suggesting that tumor cells in vivo exhibit the plasticity to switch between single and collective cell migration.

Tumorigenesis is largely driven by the subversion of normal cellular processes that control cell proliferation and cell death. It is therefore not entirely surprising that molecular mechanisms that control cellular motility in normal physiology reappear in metastatic cancer. However, unlike normal migrating cells, metastatic tumor cells no longer respond to contact inhibition and are capable of crossing barriers that are non-permissive to normal cells.

Section snippets

Tumor cell motility is a therapeutically viable target for the treatment of metastasis

Despite the growing evidence implicating tumor cell motility in metastasis, there remains uncertainty about the viability of targeting motility with the intent of treating metastasis. There is evidence for both active and passive mechanisms of cancer dissemination [7], [8]. Furthermore it has been suggested that the transient contribution of tumor cell motility to metastasis does not make it a suitable clinical target [7]. These factors raise the question: can the inhibition of motility

Metastasis and the role of tumor cell motility

In order for a tumor cell to disseminate to a distant site, it must detach from the primary lesion, invade locally, and travel to a distant site where it can survive and proliferate (Fig. 3). Dissemination occurs via three avenues: 1) local invasion of normal tissues adjacent to the tumor, 2) infiltration of the draining lymphatic system, or 3) hematogenous metastasis through the vasculature [7]. Although large numbers of circulating tumor cells can be detected in tumor-bearing animals,

Acknowledgments

We want to recognize Kristin H. Kain for critical review of the manuscript. Trenis Palmer was supported by the National Institutes of Health under the Ruth L. Kirschstein National Research Service Award (F31 National Cancer Institute). This work was partially supported by CCSRI Grant #700537 to JDL as well as NIH/NCI Grant #CA120711-01A1 and CA143081-01 to AZ.

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