Trends in Cell Biology
Volume 27, Issue 1, January 2017, Pages 12-25
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Review
Special Issue: Cell Cycle
Divide or Conquer: Cell Cycle Regulation of Invasive Behavior

https://doi.org/10.1016/j.tcb.2016.08.003Get rights and content

Trends

Cell-invasive behavior is critical during development and is dysregulated in disease states, including cancer metastasis.

The ability to adopt an invasive phenotype and breach a mechanical barrier such as the basement membrane may be regulated in a cell cycle-dependent fashion. This underlies a dichotomy between cell proliferation and cell invasion.

Invasion occurs primarily in a G1/G0 cell cycle-arrested state, and expression of proinvasive genes driving epithelial to mesenchymal transition and F-actin cytoskeletal reorganization are associated with this cell cycle state.

Changes in the activity of cyclin-dependent kinase inhibitors and their target cyclins and cyclin-dependent kinases not only mediate the decision to enter or exit the cell cycle, but also may be critical to acquiring an invasive phenotype.

Therapeutics that cause G1/G0 arrest, such as palbociclib, show great promise, but further research is required to ensure that these drugs do not inadvertently drive metastatic cancer progression.

Cell invasion through the basement membrane (BM) occurs during normal embryonic development and is a fundamental feature of cancer metastasis. The underlying cellular and genetic machinery required for invasion has been difficult to identify, due to a lack of adequate in vivo models to accurately examine invasion in single cells at subcellular resolution. Recent evidence has documented a functional link between cell cycle arrest and invasive activity. While cancer progression is traditionally thought of as a disease of uncontrolled cell proliferation, cancer cell dissemination, a critical aspect of metastasis, may require a switch from a proliferative to an invasive state. In this work, we review evidence that BM invasion requires cell cycle arrest and discuss the implications of this concept with regard to limiting the lethality associated with cancer metastasis.

Section snippets

Linking Cell Invasion and Cell Cycle Regulation

The basement membrane (BM; see Glossary), or basal lamina, is a specialized form of extracellular matrix and a metazoan innovation 1, 2 that likely helped support the evolution of the three-dimensional body plan 3, 4. Structurally composed of polymeric laminin and crosslinked type IV collagen networks, the BM is a thin, dense, sheetlike material that provides structural support for epithelial and endothelial tissues and functions as a barrier limiting cellular movement [5]. However, specific

Cell Cycle Regulation of Invasion During Development

Invasive behavior is a critical component of metazoan development. This section reviews literature that suggests that the acquisition of invasive behavior during development is specifically regulated in a cell cycle-dependent fashion. During mammalian embryo implantation (Figure 1A), cytotrophoblasts, the first embryonic cell type to exhibit highly specialized functions, differentiate into extravillous trophoblasts, which then invade into the uterine lining, as the first step of placentation

Development and Cancer: Two Sides of the Same Coin

Cancer cells hijack developmental regulatory programs and signaling pathways to execute the suite of behaviors required for metastasis. Thus, the same morphogenetic cell biological behaviors and molecular cues that are required for developmental processes such as gastrulation and neural crest delamination during embryogenesis are also utilized by tumor cells to proliferate, communicate with the surrounding microenvironment, and adopt an invasive phenotype [47]. For processes like cell invasion,

Therapeutic Implications of Cell Cycle Regulation of Invasive Behavior

Traditional antineoplastic chemotherapeutics kill rapidly dividing cells. However, since invasive cells appear to exist in quiescent G1/G0 arrest (Table 1), these invasive, metastatic cell populations remain when the bulk of the tumor is killed by classical antineoplastics. For example, sublethal irradiation, which blocks the G1/S phase checkpoint, increases the metastatic potential of gliomas [98]. Further research is necessary to determine if cell cycle arrest triggered by sublethal doses of

Concluding Remarks

We have reviewed literature demonstrating that a broad array of cancers switch between invasive and proliferative states, with evidence ranging from correlative Matrigel invasion assays to histopathological studies of primary tumor samples (Table 1). Together, these data argue that cell cycle arrest may be a requirement for the acquisition of invasive activity. Given recent functional data from a developmental invasion event in C. elegans, we suggest that G1/G0 phase cell cycle arrest may be

Acknowledgments

The authors would like to thank Mathieu Boissan, R. Antonio Herrera, and Taylor Medwig for their feedback, as well as the two anonymous reviewers, whose comments greatly improved the manuscript. We also thank Taylor Medwig for confocal micrographs used in Figure 1. D.Q.M. is supported by the Carol M. Baldwin Foundation for Breast Cancer Research and by the National Institutes of Health, National Cancer Institute (R00-CA154870).

Glossary

Basement membrane
a dense highly crosslinked sheet of polymeric laminin and type IV collagen forming the substrate for endothelia and epithelia and providing a barrier function for most cells.
Basement membrane invasion
the process by which cells remove basement membrane allowing contact between cell layers or passage through the basement membrane.
Caenorhabditis elegans anchor cell invasion
an in vivo model system used to examine the process of basement membrane invasion, as a specialized somatic

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