Elsevier

Pharmacological Reports

Volume 67, Issue 4, August 2015, Pages 711-718
Pharmacological Reports

Review article
Endothelium and cancer metastasis: Perspectives for antimetastatic therapy

https://doi.org/10.1016/j.pharep.2015.05.014Get rights and content

Abstract

Endothelial cells accompany the malignant cancer cell in almost every stage of metastatic process which includes: infiltration of tumor cells into the neighboring tissue, transmigration through endothelium (intravasation), survival in the blood stream, and extravasation followed by colonization of the target organ. The blood vessels within the tumor are heterogeneous, highly permeable, and chaotically branched therefore often described as abnormal or dysfunctional. These abnormalities are common for all components of the vessel wall and result from the activity of such factors as hypoxia and chronic growth factor stimulation. In this review, we focus not only on the distinctions in terms of the characteristic and function of tumor endothelial cells (TEC) as compared to normal endothelial cells (NEC), but also on all of these metastasis steps, which are accompanied by endothelial mediated mechanisms. Moreover, some therapeutic approaches directly or indirectly targeting the endothelium are discussed.

Section snippets

Metastatic cascade

Metastases, the main cause of cancer-related deaths arise from a primary lesion as a result of the multistep, complex process referred to as metastatic cascade. Metastasis is initiated when non-invasive cells of a primary tumor following genetic and epigenetic changes acquire their metastatic potential, detach from tumor mass and invade neighboring tissue in order to reach the nearest blood vessel. After transmigration through the vessel wall barrier (intravasation), invasive cells while being

Vascular endothelium in the early stages of tumor invasiveness and metastasis: angiogenesis and intravasation

Rapid growth of tumors eventually leads to insufficiency of oxygen and nutrients supply. Reaching that critical point tumor cells within neoplastic mass either remain dormant (proliferate and undergo apoptosis at the equal rate) or during phenomenon called “angiogenic switch” they aquire pro-angiogenic phenotype and actively recruit new vessels. Newly formed blood vessels not only enable tumor mass to grow further but also provide routes for metastatic spread throughout the body system [6].

Activation loop between the endothelium, platelets and tumor cells: survival in blood stream

Tumor-associated endothelium activation, hypoxia and ROS or disruption of endothelial integrity may result in enhanced blood coagulation that is commonly attributed to malignant cancers. The direct linkage between hypoxia and platelets activity has not been fully recognized yet; however, it has been shown that VEGF one of the key factors expressed in response to hypoxia may potentiate activation of platelets [43]. What is more, disrupted endothelium continuity occurring in the course of cancer

The role of the vascular endothelium in the latter stages of tumor metastasis: extravasation and colonization

Described above disruption of endothelium integrity observed in malignant cancer activate various defense mechanisms including leukocyte recruitment. Moreover, tumor-stimulated EC express chemokines, cytokines, and adhesion molecules playing a crucial role in the leukocyte–endothelial cell interaction and further promote recruitment of immune cells such as monocytes and neutrophils (Fig. 1). The latter are involved in tumor cell adhesion to ECs and thereby facilitate their extravasation [73].

Pathological activity of endothelium as a promising target for novel antimetastatic therapies

Since it has been proved that the development of malignant cancer is accompanied by disrupted blood hemostasis and endothelial activation, a restoration of normal conditions in the vascular system appears to be an encouraging aim for novel anticancer therapies targeting the pathological activity of the endothelium.

The hypothesis that inhibition of pathological tumor vessel formation would attenuate tumor progression seems to be beyond doubt. To date, a number of potential drugs with different

Conflict of interest

The authors declare that there are no conflicts of interests.

Funding

This work was supported by European Union from the resources of the European Regional Development Fund under the Innovative Economy Programme (grant coordinated by JCET-UJ, No POIG.01.01.02-00-069/09).

References (109)

  • J.R. Van Beijnum et al.

    Gene expression of tumor angiogenesis dissected: specific targeting of colon cancer angiogenic vasculature

    Blood

    (2006)
  • F. Van Zijl et al.

    Initial steps of metastasis: cell invasion and endothelial transmigration

    Mutat Res

    (2011)
  • M. Haidari et al.

    Disruption of endothelial adherens junction by invasive breast cancer cells is mediated by reactive oxygen species and is attenuated by AHCC

    Life Sci

    (2013)
  • E.M. Conn et al.

    Comparative analysis of metastasis variants derived from human prostate carcinoma cells: roles in intravasation of VEGF-mediated angiogenesis and uPA-mediated invasion

    Am J Pathol

    (2009)
  • F. Selheim et al.

    Identification of functional VEGF receptors on human platelets

    FEBS Lett

    (2002)
  • J.N. George

    Platelets

    Lancet

    (2000)
  • E.M. Battinelli et al.

    Release of angiogenesis regulatory proteins from platelet alpha granules: modulation of physiologic and pathologic angiogenesis

    Blood

    (2011)
  • H.M. Verheul et al.

    Vascular endothelial growth factor-stimulated endothelial cells promote adhesion and activation of platelets

    Blood

    (2000)
  • E.M. Battinelli et al.

    Anticoagulation inhibits tumor cell-mediated release of platelet angiogenic proteins and diminishes platelet angiogenic response

    Blood

    (2014)
  • T. Miyashita et al.

    Metastasis-promoting role of extravasated platelet activation in tumor

    J Surg Res

    (2015)
  • M. Labelle et al.

    Direct signaling between platelets and cancer cells induces an epithelial–mesenchymal-like transition and promotes metastasis

    Cancer Cell

    (2011)
  • J.S. Palumbo et al.

    Platelets and fibrin(ogen) increase metastatic potential by impeding natural killer cell-mediated elimination of tumor cells

    Blood

    (2005)
  • O. Barreiro et al.

    Molecular basis of leukocyte–endothelium interactions during the inflammatory response

    Rev Esp Cardiol Engl Ed

    (2009)
  • J.T. Erler et al.

    Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the pre-metastatic niche

    Cancer Cell

    (2009)
  • H. Läubli et al.

    Selectin-mediated activation of endothelial cells induces expression of CCL5 and promotes metastasis through recruitment of monocytes

    Blood

    (2009)
  • J.M. Walenga et al.

    Evolution of heparin anticoagulants to ultra-low-molecular-weight heparins: a review of pharmacologic and clinical differences and applications in patients with cancer

    Crit Rev Oncol Hematol

    (2013)
  • H.A. Hadi et al.

    Endothelial dysfunction: cardiovascular risk factors, therapy, and outcome

    Vasc Health Risk Manag

    (2005)
  • J.K. Liao

    Linking endothelial dysfunction with endothelial cell activation

    J Clin Invest

    (2013)
  • D.H. Endemann et al.

    J Am Soc Nephrol

    (2004)
  • P.S. Steeg

    Tumor metastasis: mechanistic insights and clinical challenges

    Nat Med

    (2006)
  • N. Masson et al.

    Hypoxia signaling pathways in cancer metabolism: the importance of co-selecting interconnected physiological pathways

    Cancer Metab

    (2014)
  • E.M. De Francesco et al.

    HIF-1α/GPER signaling mediates the expression of VEGF induced by hypoxia in breast cancer associated fibroblasts (CAFs)

    Breast Cancer Res

    (2013)
  • A. Bruno et al.

    Orchestration of angiogenesis by immune cells

    Front Oncol

    (2014)
  • W. Hilbe et al.

    CD133 positive endothelial progenitor cells contribute to the tumour vasculature in non-small cell lung cancer

    J Clin Pathol

    (2004)
  • Y.S. Chang et al.

    Mosaic blood vessels in tumors: frequency of cancer cells in contact with flowing blood

    Proc Natl Acad Sci U S A

    (2000)
  • K. Hida et al.

    Heterogeneity of tumor endothelial cells

    Cancer Sci

    (2013)
  • M.M. Darpolor et al.

    Multimodality imaging of abnormal vascular perfusion and morphology in preclinical 9L gliosarcoma model

    PLoS ONE

    (2011)
  • Y. Xu et al.

    Endothelial cell targeted molecular imaging in tumor angiogenesis: strategies and current status

    Curr Pharm Biotechnol

    (2013)
  • D.N. Amin et al.

    Tumor endothelial cells express epidermal growth factor receptor (EGFR) but not ErbB3 and are responsive to EGF and to EGFR kinase inhibitors

    Cancer Res

    (2006)
  • K. Tsuchiya et al.

    Adrenomedullin antagonist suppresses tumor formation in renal cell carcinoma through inhibitory effects on tumor endothelial cells and endothelial progenitor mobilization

    Int J Oncol

    (2010)
  • B. Bussolati et al.

    Altered angiogenesis and survival in human tumor-derived endothelial cells

    FASEB J

    (2003)
  • Y.-Q. Xiong et al.

    Human hepatocellular carcinoma tumor-derived endothelial cells manifest increased angiogenesis capability and drug resistance compared with normal endothelial cells

    Clin Cancer Res

    (2009)
  • R. Pasqualini et al.

    Profiling the molecular diversity of blood vessels

    Cold Spring Harb Symp Quant Biol

    (2002)
  • B. St Croix et al.

    Genes expressed in human tumor endothelium

    Science

    (2000)
  • J.D. Spicer et al.

    Neutrophils promote liver metastasis via Mac-1-mediated interactions with circulating tumor cells

    Cancer Res

    (2012)
  • J.B. Wyckoff et al.

    Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors

    Cancer Res

    (2007)
  • Q. Shen et al.

    Tissue inhibitor of metalloproteinase-2 regulates matrix metalloproteinase-2-mediated endothelial barrier dysfunction and breast cancer cell transmigration through lung microvascular endothelial cells

    Mol Cancer Res

    (2010)
  • I.K. Zervantonakis et al.

    Three-dimensional microfluidic model for tumor cell intravasation and endothelial barrier function

    Proc Natl Acad Sci U S A

    (2012)
  • J. Wyckoff et al.

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

    Cancer Res

    (2004)
  • A. Patsialou et al.

    Invasion of human breast cancer cells in vivo requires both paracrine and autocrine loops involving the colony-stimulating factor-1 receptor

    Cancer Res

    (2009)
  • Cited by (0)

    View full text