Trends in Cell Biology
Volume 15, Issue 3, March 2005, Pages 138-145
Journal home page for Trends in Cell Biology

Tumor cells caught in the act of invading: their strategy for enhanced cell motility

https://doi.org/10.1016/j.tcb.2005.01.003Get rights and content

Invasion of neighboring extracellular matrix tissue, the lymphatic system and blood vessels is a key element of tumor cell metastasis in many epithelial tumors. Understanding the cell motility pathways that contribute to invasion can provide new approaches and targets for anticancer therapy. The recent convergence of technologies for expression profiling and intravital imaging has revealed the identities of some of the genes that contribute to motility and chemotaxis of cancer cells in tumors. In particular, the genes encoding a minimum motility machine are coordinately upregulated in tumor cells collected by an in vivo invasion assay. These results support a ‘tumor microenvironment invasion model’ and provide new target opportunities for cancer therapy.

Introduction

The ability of cancer cells to spread from primary tumors gives rise to a growing tumor burden that is distributed across several sites in the body, resulting in death for many individuals with cancer. Understanding the cellular steps that are used by cancer cells during spreading can form the basis for new ideas for diagnostic, prognostic and therapeutic approaches that might facilitate control over cancer metastasis (see Glossary).

Spreading to other organs relies on cell motility and the invasion of neighboring connective tissue, the lymphatic system and blood vessels. Cell motility has been implicated in the spreading of cancer cells 1, 2, 3 and is an essential step in metastasis 4, 5, 6, 7, 8. The invasive process can be enhanced by chemotaxis, in which a gradient of extracellular compounds (often growth factors) is detected by intracellular signal processing pathways, which in turn coordinate cell movement along the gradient 9, 10. For amoeboid cells such as tumor cells, cell motility relies on the actin-based cytoskeleton for both generating protrusions and retracting the rear of the cell in order to generate a motility cycle that results in net translocation 8, 11.

Although cell migration and chemotaxis have been studied intensively by in vitro assays, intravital imaging has been recently used to define the details of cancer cell migration in vivo and this technique has led to several new insights into differences in motility that cancer cells show in tumors as compared with their behavior in culture. The increase in speed and linearity of movement of a subset of tumor cells towards blood vessels in vivo is in marked contrast to the typically slow random movement of cells in culture [10]. In addition, tumor cells can use several modes of motility, such as fibroblastic or amoeboid movement, enabling them to invade surrounding tissues of varying matrix density [74]. These features of cancer cells indicate that the phenotype of cell motility is readily adaptable to the microenvironment in which the cells find themselves. The primary tumor is composed of several microenvironments and possibly only a few tumor cells are actively invading at any one time. Thus, bulk analyses of primary tumor properties might not adequately describe the characteristics of invading tumor cells.

The tremendous variation among human cancers implies that specific pathways or mechanisms of growth, apoptosis or metastasis are likely to be important for only a subset of tumor types. In this review, we describe our studies to identify the gene expression patterns that are present in invasive tumor cells as an approach to defining strategies to impede the spread of cancer cells from tumors. We have placed our emphasis on motility-related genes in order to focus on a potentially rich source of new targets specifically related to metastasis in the face of the overwhelming amount of data that is typically generated in microarray-based studies.

We first summarize the studies of other research groups that have analyzed the expression patterns of invasive and metastatic tumors and highlight the difficulties that are inherent in specifically analyzing invading tumor cells. We then discuss our studies that are based on an alternative approach to isolating invasive tumor cells – namely, the in vivo invasion assay. These studies reinforce the concept that changes in the expression status of pathways can be a valuable way in which to interpret variations in gene expression. We conclude with a description of the tumor microenvironment invasion model, which might help us to define how we think about tumor invasion.

Section snippets

Expression analysis of invasive and metastatic tumors

A chief goal of microarray-based expression tumor analysis is to identify genes that are involved in metastasis and patterns of gene expression that will give an indication of the likelihood of metastasis [12]. An ability to predict whether a given primary tumor is likely to have metastasized would have direct effects on therapy design for an individual with cancer. Most studies have concentrated on the analysis of bulk tumor samples that incorporate other tissue elements, including supporting

Chemotaxis and the in vivo invasion assay

Our research group has approached the challenge of directly collecting tumor cells during the invasion step by making use of one of the properties that is likely to be important for invasion metastasis – namely, chemotaxis [19]. Chemotaxis to blood vessels facilitates the intravasation of cancer cells and their systemic spread. Chemotaxis and cell migration in response to epidermal growth factor (EGF) are correlated with invasion, intravasation and metastasis in animal models of breast cancer 19

The importance of pathways that regulate protrusion in cancer invasion and metastasis

The hypothesis that genes that are differentially regulated in invasive cells contribute to the invasive and metastatic phenotype has been examined. For example, a gene that is strongly downregulated in invasive cells is zipcode-binding protein 1 (ZBP1), an RNA-binding protein of 68 kDa that binds to the mRNA zipcode of β-actin mRNA and functions to localize the mRNA to the leading edge of crawling cells. β-actin is the preferred isoform of actin for the polymerization of filaments at the

The tumor microenvironment invasion model

Gene expression profiling of whole tumors with microarrays has shown promise in prognosis by identifying patterns of expression that are correlated with metastasis 14, 46. These patterns of expression do not provide clues about the mechanisms of invasion and metastasis, however, and can appear as random sets of genes with unrelated functions. A particularly surprising feature of such profiling studies is that they support the notion that the invasive and metastatic potential of the primary

Concluding remarks

Further work on the behavior of invasive cells in vivo, and what supports their motility in vivo, will be required to test such new models of how tumors spread. A crucial prediction of the tumor microenvironment invasion model is that specific, localized patterns of gene expression in tumor cells (and potentially in stromal cells) will occur in areas of invasion. New methods of in situ hybridization that evaluate several genes simultaneously in the same cell will help to test the tumor

Acknowledgements

This activity was funded by a grant from the National Cancer Institute (CA 100324). E.S. is funded by Cancer Research UK.

Glossary

Cell invasion:
A term used in tumor biology to emphasize the pathological and inappropriate spread of tumor cells into neighboring tissues and extracellular spaces.
Cell motility:
The active extension and retraction of cell processes, such as filopods and lamellipods, that results in a net movement of the cell body. In fibroblastic movement cells form focal adhesions and make use of matrix metalloproteases, whereas in amoeboid movement cells deform markedly and squeeze through pores in the matrix

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