Review articleEndothelium and cancer metastasis: Perspectives for antimetastatic therapy
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).
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