Cancer cells remodel themselves and vasculature to overcome the endothelial barrier

doi:10.1016/j.canlet.2014.10.031

Cancer Letters

Volume 380, Issue 2, 1 October 2016, Pages 534-544

https://doi.org/10.1016/j.canlet.2014.10.031 Get rights and content

Highlights

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A variety of signaling pathways induce EMT in cancer cells.
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EMT facilitates cancer cell invasion and migration to blood vessels for intravasation.
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Cancer cells use adhesion molecules to attach to endothelium for extravasation.
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Cancer cells secrete vascular permeabilizing factors to overcome endothelial barrier.

Abstract

Metastasis refers to the spread of cancer cells from a primary tumor to distant organs mostly via the bloodstream. During the metastatic process, cancer cells invade blood vessels to enter circulation, and later exit the vasculature at a distant site. Endothelial cells that line blood vessels normally serve as a barrier to the movement of cells into or out of the blood. It is thus critical to understand how metastatic cancer cells overcome the endothelial barrier. Epithelial cancer cells acquire increased motility and invasiveness through epithelial-to-mesenchymal transition (EMT), which enables them to move toward vasculature. Cancer cells also express a variety of adhesion molecules that allow them to attach to vascular endothelium. Finally, cancer cells secrete or induce growth factors and cytokines to actively prompt vascular hyperpermeability that compromises endothelial barrier function and facilitates transmigration of cancer cells through the vascular wall. Elucidation of the mechanisms underlying metastatic dissemination may help develop new anti-metastasis therapeutics.

Introduction

Metastasis is the major reason for cancer-related deaths. It is a sequential order of events that involves invasion and migration of cancer cells from the primary site to distant organs where they eventually form secondary tumors. This multi-step process is referred to as invasion-metastasis cascade [1], [2], [3] and could be simplified into two phases: (1) Physical translocation of a cancer cell from the primary tumor to the distant tissues (secondary site). (2) Colonization of these cancer cells at the secondary site [4]. The first phase generally encompasses: (a) epithelial-to-mesenchymal transition (EMT), (b) intravasation (entry of cancer cells into the blood vessels), and (c) extravasation (exit of cancer cells from the blood vessels to invade secondary organs). EMT is a process during which epithelial cells lose their cell–cell adhesion and polarity to transform into mesenchyme-like cells [5], [6]. The hallmarks of EMT include loss of cell–cell junctions, loss of apical–basal polarity, and acquisition of migratory and invasive property [7]. Therefore, cancer cells that have undergone EMT (EMT-cancer cells) are more motile and inclined to invade the surrounding tissues. EMT-cancer cells accomplish this either as single cells or collectively in small groups [8], [9]. Following local invasion, EMT-cancer cells intravasate, resulting in dissemination of cancer cells into the blood stream [9]. Once in blood circulation, these cancer cells are referred to as circulating tumor cells (CTC). CTCs hold a prognostic significance in cancer progression as they determine the ability of the primary tumors to form distant metastatic lesions [10], [11]. CTCs that survive the shear stress and immune reactions in the blood stream extravasate through the blood vessels to colonize metastatic sites [12]. An important feature that is common to the intravasation and extravasation processes is transendothelial migration (TEM). TEM is a phenomenon by which the EMT-cancer cells cross the vascular endothelial layer [13]. Endothelial cells (ECs) normally serve as a barrier to the movement of cells into or out of the blood. However, metastatic cancer cells do cross the vascular endothelial layer during intravasation and extravasation, suggesting that the integrity of vasculature at the primary and metastatic sites may be impaired in order to facilitate TEM. In this review, we will summarize current understanding on how the process of EMT in cancer cells and the favorable modulation of vascular properties by tumor cells play a critical role in cancer cell TEM, dissemination, and metastasis (Fig. 1).

Section snippets

Epithelial-to-mesenchymal transition (EMT)

Epithelial cells are structurally well-defined cells that are linked to each other through multiple types of intercellular junctions, including adherens junctions, desmosomes, and tight junctions, to form single cell layer or multilayered tissues. These cells maintain apical–basal polarity by anchoring themselves to the underlying basement membrane via hemidesmosomes [14]. Thus, epithelial cells function as permeability barriers and play a crucial role in tissue organization and organ

Tumor vasculature and its role in metastasis

Tumor vasculature is part of tumor microenvironment. Vascular ECs have also been involved in modulation of cancer cells to consequently enhance their invasive and migratory ability. ECs have been shown to induce EMT in human pancreatic, lung and mouse breast cancer cell lines by constitutive secretion of TGFβ1 and TGFβ2 [110]. Sigurdsson et al. shows that ECs are potent inducers of EMT in basal-like breast cancer cells [111]. ECs also induce EMT in squamous cell carcinoma (SCC) cells by

Modulation of vascular property during metastasis

For metastasis to occur, cancer cells must leave the primary tumor, enter and exit the circulation, and then colonize distant sites. Vascular endothelial layer forms an important barrier for the cancer cells to leave the tumor (intravasation) and gain entry into the prospective metastatic organ (extravasation). This process of crossing the endothelial layer is termed as TEM and is the main crux of intravasation and extravasation processes [118]. Angiogenesis or formation of new blood vessels is

Why might an understanding of EMT-cancer cell and vasculature relationship be important clinically?

EMT and vascular modulation are two processes that are critical for successful metastasis. Various regulatory pathways of the two processes constantly crosstalk (Fig. 1). Inhibition of pathways involved in one process may activate the other, facilitating the events of metastasis. This could be exemplified by anti-angiogenic treatment, a commonly used adjuvant therapy for tumor growth inhibition. Anti-angiogenic therapy may have a devastating effect on metastatic progression. Treatment with

Funding

The work was in part funded by NIH (R01CA137021) and Florida Department of Health (4KB07, 2BT01).

Conflict of interest

The authors declare there is no conflict of interest.

References (248)

S. Valastyan et al.
Tumor metastasis: molecular insights and evolving paradigms
Cell
(2011)
J.P. Thiery et al.
Epithelial-mesenchymal transitions in development and disease
Cell
(2009)
D. Spano et al.
Molecular networks that regulate cancer metastasis
Semin. Cancer Biol
(2012)
F. van Zijl et al.
Initial steps of metastasis: cell invasion and endothelial transmigration
Mutat. Res
(2011)
K. Lee et al.
New insights into the regulation of epithelial-mesenchymal transition and tissue fibrosis
Int. Rev. Cell Mol. Biol
(2012)
I.J. Fidler
The organ microenvironment and cancer metastasis
Differentiation
(2002)
L.A. Shuman Moss et al.
Matrix metalloproteinases: changing roles in tumor progression and metastasis
Am. J. Pathol
(2012)
S.A. Mani et al.
The epithelial-mesenchymal transition generates cells with properties of stem cells
Cell
(2008)
K. Sampieri et al.
Cancer stem cells and metastasis
Semin. Cancer Biol
(2012)
J.H. Tsai et al.
Spatiotemporal regulation of epithelial-mesenchymal transition is essential for squamous cell carcinoma metastasis
Cancer Cell
(2012)

T. Shibue et al.

Metastatic colonization: settlement, adaptation and propagation of tumor cells in a foreign tissue environment

Semin. Cancer Biol

(2011)

J.D. Potts et al.

Epithelial-mesenchymal cell transformation in the embryonic heart can be mediated, in part, by transforming growth factor beta

Dev. Biol

(1989)

W. Cui et al.

TGFbeta1 inhibits the formation of benign skin tumors, but enhances progression to invasive spindle carcinomas in transgenic mice

Cell

(1996)

A. Moustakas et al.

TGFβ and matrix-regulated epithelial to mesenchymal transition

Biochim. Biophys. Acta

(2014)

P. Lampropoulos et al.

TGF-beta signalling in colon carcinogenesis

Cancer Lett

(2012)

C. Scheel et al.

Paracrine and autocrine signals induce and maintain mesenchymal and stem cell states in the breast

Cell

(2011)

V.G. Cooke et al.

Article pericyte depletion results in hypoxia-associated epithelial-to-mesenchymal transition and metastasis mediated by met signaling pathway

Cancer Cell

(2012)

L. Zhang et al.

Hypoxia induces epithelial-mesenchymal transition via activation of SNAI1 by hypoxia-inducible factor-1α in hepatocellular carcinoma

BMC Cancer

(2013)

D.X. Nguyen et al.

WNT/TCF signaling through LEF1 and HOXB9 mediates lung adenocarcinoma metastasis

Cell

(2009)

H. Kim et al.

Ras promotes transforming growth factor-β (TGF-β)-induced epithelial-mesenchymal transition via a leukotriene B4 receptor-2-linked cascade in mammary epithelial cells

J. Biol. Chem

(2014)

F. Strutz et al.

Role of basic fibroblast growth factor-2 in epithelial-mesenchymal transformation

Kidney Int

(2002)

J.E. Talmadge et al.

AACR centennial series: the biology of cancer metastasis: historical perspective

Cancer Res

(2010)

I.J. Fidler

The pathogenesis of cancer metastasis: the “seed and soil” hypothesis revisited

Nat. Rev. Cancer

(2003)

C.L. Chaffer et al.

A perspective on cancer cell metastasis

Science

(2011)

M.A. Nieto

The ins and outs of the epithelial to mesenchymal transition in health and disease

Annu. Rev. Cell Dev. Biol

(2011)

M.A. Nieto

Epithelial plasticity: a common theme in embryonic and cancer cells

Science

(2013)

D.X. Nguyen et al.

Metastasis: from dissemination to organ-specific colonization

Nat. Rev. Cancer

(2009)

M. Balic et al.

Circulating tumor cells: from bench to bedside

Annu. Rev. Med

(2013)

J. Scott et al.

Unifying metastasis – integrating intravasation, circulation and end-organ colonization

Nat. Rev. Cancer

(2012)

Y. Kienast et al.

Real-time imaging reveals the single steps of brain metastasis formation

Nat. Med

(2010)

J.H. Tsai et al.

Epithelial-mesenchymal plasticity in carcinoma metastasis

Genes Dev

(2013)

R.Y.-J. Huang et al.

Early events in cell adhesion and polarity during epithelial-mesenchymal transition

J. Cell Sci

(2012)

S. Lamouille et al.

Molecular mechanisms of epithelial-mesenchymal transition

Nat. Rev. Mol. Cell Biol

(2014)

M. Zeisberg et al.

Biomarkers for epithelial-mesenchymal transitions

J. Clin. Invest

(2009)

E. Sánchez-Tilló et al.

EMT-activating transcription factors in cancer: beyond EMT and tumor invasiveness

Cell. Mol. Life Sci

(2012)

B.Y. Reddy et al.

The microenvironmental effect in the progression, metastasis, and dormancy of breast cancer: a model system within bone marrow

Int. J. Breast Cancer

(2012)

I.-K. Choi et al.

Strategies to increase drug penetration in solid tumors

Front. Oncol

(2013)

A. Bergman et al.

Invadopodia in context

Cell Adh. Migr

(2014)

R. Kalluri et al.

Epithelial-mesenchymal transition and its implications for fibrosis

J. Clin. Invest

(2003)

C.J. Creighton et al.

Epithelial-mesenchymal transition (EMT) in tumor-initiating cells and its clinical implications in breast cancer

J. Mammary Gland Biol. Neoplasia

(2010)

T. Blick et al.

Epithelial mesenchymal transition traits in human breast cancer cell lines parallel the CD44(hi/)CD24 (lo/-) stem cell phenotype in human breast cancer

J. Mammary Gland Biol. Neoplasia

(2010)

D. Sarrio et al.

Epithelial and mesenchymal subpopulations within normal basal breast cell lines exhibit distinct stem cell/progenitor properties

Stem Cells

(2012)

C.J. Creighton et al.

The role of epithelial-mesenchymal transition programming in invasion and metastasis: a clinical perspective

Cancer Manag. Res

(2013)

A.V. Salnikov et al.

Hypoxia induces EMT in low and highly aggressive pancreatic tumor cells but only cells with cancer stem cell characteristics acquire pronounced migratory potential

PLoS ONE

(2012)

C. Xue et al.

The gatekeeper effect of epithelial-mesenchymal transition regulates the frequency of breast cancer metastasis

Cancer Res

(2003)

N. Erez et al.

Leukocytes as paracrine regulators of metastasis and determinants of organ-specific colonization

Int. J. Cancer

(2011)

R. Kalluri et al.

The basics of epithelial-mesenchymal transition

J. Clin. Invest

(2009)

P.J. Miettinen et al.

TGF-beta induced transdifferentiation of mammary epithelial cells to mesenchymal cells: involvement of type I receptors

J. Cell Biol

(1994)

G. Giannelli et al.

Transforming growth factor-β as a therapeutic target in hepatocellular carcinoma

Cancer Res

(2014)

B.T. Vo et al.

TGF-β effects on prostate cancer cell migration and invasion are mediated by PGE2 through activation of PI3K/AKT/mTOR pathway

Endocrinology

(2013)

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Mini-reviewCancer cells remodel themselves and vasculature to overcome the endothelial barrier

Highlights

Abstract

Introduction

Section snippets

Epithelial-to-mesenchymal transition (EMT)

Tumor vasculature and its role in metastasis

Modulation of vascular property during metastasis

Why might an understanding of EMT-cancer cell and vasculature relationship be important clinically?

Funding

Conflict of interest

Cell

Cell

Semin. Cancer Biol

Mutat. Res

Int. Rev. Cell Mol. Biol

Differentiation

Am. J. Pathol

Cell

Semin. Cancer Biol

Cancer Cell

Semin. Cancer Biol

Dev. Biol

Cell

Biochim. Biophys. Acta

Cancer Lett

Cell

Cancer Cell

BMC Cancer

Cell

J. Biol. Chem

Kidney Int

AACR centennial series: the biology of cancer metastasis: historical perspective

Cancer Res

The pathogenesis of cancer metastasis: the “seed and soil” hypothesis revisited

Nat. Rev. Cancer

A perspective on cancer cell metastasis

Science

The ins and outs of the epithelial to mesenchymal transition in health and disease

Annu. Rev. Cell Dev. Biol

Epithelial plasticity: a common theme in embryonic and cancer cells

Science

Metastasis: from dissemination to organ-specific colonization

Nat. Rev. Cancer

Circulating tumor cells: from bench to bedside

Annu. Rev. Med

Unifying metastasis – integrating intravasation, circulation and end-organ colonization

Nat. Rev. Cancer

Real-time imaging reveals the single steps of brain metastasis formation

Nat. Med

Epithelial-mesenchymal plasticity in carcinoma metastasis

Genes Dev

Early events in cell adhesion and polarity during epithelial-mesenchymal transition

J. Cell Sci

Molecular mechanisms of epithelial-mesenchymal transition

Nat. Rev. Mol. Cell Biol

Biomarkers for epithelial-mesenchymal transitions

J. Clin. Invest

EMT-activating transcription factors in cancer: beyond EMT and tumor invasiveness

Cell. Mol. Life Sci

The microenvironmental effect in the progression, metastasis, and dormancy of breast cancer: a model system within bone marrow

Int. J. Breast Cancer

Strategies to increase drug penetration in solid tumors

Front. Oncol

Invadopodia in context

Cell Adh. Migr

Epithelial-mesenchymal transition and its implications for fibrosis

J. Clin. Invest

Epithelial-mesenchymal transition (EMT) in tumor-initiating cells and its clinical implications in breast cancer

J. Mammary Gland Biol. Neoplasia

Epithelial mesenchymal transition traits in human breast cancer cell lines parallel the CD44(hi/)CD24 (lo/-) stem cell phenotype in human breast cancer

J. Mammary Gland Biol. Neoplasia

Epithelial and mesenchymal subpopulations within normal basal breast cell lines exhibit distinct stem cell/progenitor properties

Stem Cells

The role of epithelial-mesenchymal transition programming in invasion and metastasis: a clinical perspective

Cancer Manag. Res

Hypoxia induces EMT in low and highly aggressive pancreatic tumor cells but only cells with cancer stem cell characteristics acquire pronounced migratory potential

PLoS ONE

The gatekeeper effect of epithelial-mesenchymal transition regulates the frequency of breast cancer metastasis

Cancer Res

Mini-review
Cancer cells remodel themselves and vasculature to overcome the endothelial barrier