Cell migration in tumors

doi:10.1016/j.ceb.2005.08.002

Current Opinion in Cell Biology

Volume 17, Issue 5, October 2005, Pages 559-564

https://doi.org/10.1016/j.ceb.2005.08.002 Get rights and content

Invasion of cancer cells into surrounding tissue and the vasculature is an initial step in tumor metastasis. This requires chemotactic migration of cancer cells, steered by protrusive activity of the cell membrane and its attachment to the extracellular matrix. Recent advances in intravital imaging and the development of an in vivo invasion assay have provided new insights into how cancer cell migration is regulated by elements of the local microenvironment, including the extracellular matrix architecture and other cell types found in primary tumors. These results, combined with new findings from in vitro studies, have led to new insights into the molecular mechanisms of cell protrusive activity and chemotactic migration during invasion and metastasis.

Introduction

Metastasis — the dissemination of cancer cells from the primary tumor to a distant organ — is the most frequent cause of death for patients with cancer. However, the molecular mechanisms of metastasis are poorly understood as a result of their apparent complexity. Cancer cell migration and invasion into adjacent tissues and intravasation into blood/lymphatic vessels are required for metastasis of adenocarcinomas, the most common human cancers [1, 2]. Invasive carcinoma cells acquire a migratory phenotype associated with increased expression of several genes involved in cell motility [3•, 4]. This allows carcinoma cells to respond to cues from the microenvironment that trigger tumor invasion. Therefore, molecules involved in cancer cell migration could be potential targets for anti-metastasis therapy. However, most studies on cell motility have been performed in two-dimensional (2D) culture systems, which limits our understanding of mechanisms of cell migration, as cells use different cell migration strategies in physiological three-dimensional (3D) culture systems [5, 6]. Moreover, recent advances in in vivo imaging have yielded new insights into the migration of carcinoma and host cells in tumors and demonstrate that the regulation of cancer cell migration in vivo is more complicated than had been supposed, involving chemoattractants, the extracellular matrix, and signaling interactions with stromal cells [2, 7••, 8].

In this review, we summarize recent progress uncovering how mammary carcinoma cells migrate in primary tumors and how the migration is regulated by macrophages. We also integrate recent findings on molecular mechanisms of carcinoma cell and macrophage migration, with emphasis on the protrusive structures formed by these cell types that steer the cells toward blood vessels and that facilitate invasion and intravasation.

Section snippets

Cancer cell migration on and through the extracellular matrix in tumors in vivo

Cancer cell migration in primary tumors can be directly observed by multiphoton microscopy with animals carrying green fluorescent protein (GFP)-labeled tumors [7^••]. In the case of breast tumors, most of the migrating cells are solitary with an amoeboid morphology [9]. These cells are often observed moving linearly in association with the extracellular matrix (ECM) fibers (Figure 1a). Given that some of the ECM fibers converge onto blood vessels, these fibers function as a path for carcinoma

A paracrine loop between cancer cells and macrophages

Tumor progression and invasion are controlled by crosstalk between cancer cells and other cell types within the tumor and the surrounding tissue. The presence of tumor-associated macrophages in primary tumors has been associated with increased metastasis [10]. Using a chemotaxis-based in vivo invasion assay, it was revealed that a paracrine loop between carcinoma cells and macrophages facilitates invasion of carcinoma cells in the primary tumor [11^••]. In the in vivo invasion assay, when

Cell protrusions for cell migration in tumors: lamellipodia and invadopodia/podosomes

The initial step in cell migration is the protrusion of the cell membrane. This is driven by localized actin polymerization [14] and can occur in response to chemotactic signals [15]. Carcinoma cells crawling on ECM fibers in primary tumors extend pseudopods that attach to the fibers at the migration front [7^••]. The pseudopods seem to be functionally equivalent to lamellipodia (sheet-like protrusions observed in cells migrating on 2D substrate in vitro), although the shapes of pseudopods are

Conclusions

Mechanisms of cell migration in tumors have been unveiled by the use of new technologies such as intravital imaging and in vivo invasion assays. In vitro studies using 3D cell culture systems have revealed new aspects of cancer cell migration and focused our attention on specialized protrusions involved in chemotaxis and ECM invasion. Nevertheless, 2D cell culture still provides important insights into the molecular basis of cell protrusions, chemotaxis and cell polarity. Therefore, the

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

• of special interest
•• of outstanding interest

Acknowledgements

We apologize to those authors whose work we were unable to cite because of space and date of publication limitations. We are grateful to all laboratory members and collaborators for their support and helpful discussions. We thank M Sidani for intravital imaging pictures. This work was supported by grants from the NIH (GM38511 and CA100324).

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The mechanical properties of the tumor microenvironment significantly influence cancer cell migration within the primary tumor, yet how these properties affect intercellular interactions in heterogeneous tumors is not well understood. By utilizing calcium and calcium chelators, we dynamically alter collagen-alginate hydrogel stiffness and investigate tumor cell behavior within co-culture spheroids in response to varying degrees of matrix confinement. High confinement is found to trigger cell sorting while reducing confinement for sorted spheroids facilitates collective cell invasion. Notably, without prior sorting, spheroids do not exhibit burst-like migration, regardless of confinement levels. This work establishes that matrix confinement and intercellular adhesion regulate 3D spheroid dynamics, offering insights into cellular organization and migration within the primary tumor.
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Gemcitabine (GEM) is a standard chemotherapeutic agent for patients with pancreatic cancer; however, GEM-based chemotherapy has a high rate of toxicity. A combination of GEM and active constituents from natural products may enhance its therapeutic efficacy and reduce its toxicity. This study investigated the synergistic effects of the combination of liriopesides B (LirB) from Liriope spicata var. prolifera and GEM on human pancreatic cancer cells. The results of our study showed that the combination of LirB and GEM synergistically decreased the viability of pancreatic cancer cells. The combination also caused a strong increase in apoptosis and a strong decrease in cell migration and invasion. Furthermore, LirB combined with GEM had potent inhibitory effects on pancreatic cancer stem cells (CSCs). Studies on the mechanisms of action showed that the combination more potently inhibited protein kinase B (Akt) and nuclear factor kappa B (NF-κB), as well as the downstream antiapoptotic molecules B-cell lymphoma 2 (Bcl-2) and survivin than either agent used alone. The results of this study suggest that the combination of LirB with GEM may improve the efficacy of GEM for the treatment of pancreatic cancer.
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Cell migration in tumors

Introduction

Section snippets

Cancer cell migration on and through the extracellular matrix in tumors in vivo

A paracrine loop between cancer cells and macrophages

Cell protrusions for cell migration in tumors: lamellipodia and invadopodia/podosomes

Conclusions

References and recommended reading

Acknowledgements

J Cell Biol

Nat Rev Cancer

Mol Biol Cell

J Cell Biol

Exp Cell Res

J Cell Biol

Mol Biol Cell

Dissemination and growth of cancer cells in metastatic sites

Nat Rev Cancer

Tumour-cell invasion and migration: diversity and escape mechanisms

Nat Rev Cancer

Identification and testing of a gene expression signature of invasive carcinoma cells within primary mammary tumors

Cancer Res

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

Trends Cell Biol

Differing modes of tumour cell invasion have distinct requirements for Rho/ROCK signalling and extracellular proteolysis

Nat Cell Biol

Intravital imaging of cell movement in tumours

Nat Rev Cancer

Mechanisms of cancer cell invasion

Curr Opin Genet Dev

Single cell behavior in metastatic primary mammary tumors correlated with gene expression patterns revealed by molecular profiling

Cancer Res

A paracrine loop between tumor cells and macrophages is required for tumor cell migration in mammary tumors

Cancer Res

Macrophages promote the invasion of breast carcinoma cells via a CSF-1/EGF paracrine loop

Cancer Res

Regulation of matrix biology by matrix metalloproteinases

Curr Opin Cell Biol

Cellular motility driven by assembly and disassembly of actin filaments

Cell

Cofilin takes the lead

J Cell Sci

Cofilin promotes actin polymerization and defines the direction of cell motility

Science

Synergistic interaction between the Arp2/3 complex and cofilin drives stimulated lamellipod extension

J Cell Sci