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INVESTIGATIVE REPORT Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV
Placental Growth Factor and Vascular Endothelial Growth Factor Together Regulate Tumour Progression via Increased Vasculature in Cutaneous T-cell Lymphoma
Tomomitsu MIYAGAKI , Makoto SUGAYA , Tomonori OKA , Naomi TAKAHASHI , Makiko KAWAGUCHI , Hiraku SUGA , Hideki FUJITA , Ayumi YOSHIZAKI , Yoshihide ASANO and Shinichi SATO Department of Dermatology , Faculty of Medicine , University of Tokyo , Tokyo , Japan
Angiogenesis is regarded as an essential step in supporting tumour growth and metastasis . In haematological malignancies , including cutaneous T-cell lymphoma ( CTCL ), angiogenesis is increased and serum levels of some pro-angiogenic markers are elevated . The aim of this study was to investigate expression levels of placental growth factor ( PlGF ) and vascular endothelial growth factor ( VEGF ) -A in lesional skin and sera in patients with CTCL , and to assess the association of these factors with development of CTCL . A further aim was to investigate the effect of PlGF on lymphoma cell growth in vivo using a tumour inoculation model . Expression of PlGF and VEGF-A were significantly elevated in CTCL skin . Tumour cells expressed PlGF in some cases . Serum PlGF levels were increased in patients with advanced CTCL and correlated with disease markers . Moreover , PlGF enhanced lymphoma cell growth in vivo through increasing tumour vasculature . These findings suggest that angiogenesis plays a role in the progression of CTCL and raises the possibility of using inhibitors of PlGF in CTCL therapy .
Key words : placental growth factor ; cutaneous T-cell lymphoma ; angiogenesis ; disease marker .
Accepted Jan 24 , 2017 ; Epub ahead of print xx Acta Derm Venereol 2017 ; 97 : 586 – 592 .
Corr : Tomomitsu Miyagaki , Department of Dermatology , Faculty of Medicine , University of Tokyo , 7-3-1 Hongo , Bunkyo-ku , Tokyo 113-8655 , Japan . E-mail : asahikari1979 @ gmail . com
Mycosis fungoides ( MF ) and Sézary syndrome ( SS ) are the most common types of cutaneous T-cell lymphoma ( CTCL ). MF is characterized by the malignant proliferation of neoplastic CD4 + CD45RO + T cells , which preferentially traffic to the skin , and has a classically prolonged clinical course . A small proportion of cases progress over years through patch , plaque , and tumour stages , followed by lymph node and visceral involvement ( 1 ). SS is characterized by fever , erythroderma , lymphadenopathy , and leukaemic involvement , and usually has a rapid clinical course ( 2 ). Although the pathogenesis of CTCL is unknown , a variety of cytokines / chemokines are reported to be involved in development of the disease ( 3 – 5 ).
Angiogenesis , the growth of new blood vessels from pre-existing ones , is regarded as an important step to support primary and metastatic tumour growth ( 6 ). Angiogenesis is also thought to be important for the progression of haematological malignancies . Some clinical observations have indicated that tumour microvessel density , measured by CD34 , CD31 , or von Willebrand factor expression , is increased in various lymphoproliferative disorders ( 7 ). Increased serum levels of pro-angiogenic markers are also reported in some haematological malignancies ( 7 ). Similarly , in CTCL , angiogenesis , assessed either by microvessel density or by microvessel number in lesional skin , is increased , suggesting that interaction between tumour cells and their microvasculature is likely to occur during the progression of CTCL ( 8 , 9 ). Consistent with those reports , increased expression of angiogenin , one of the angiogenic factors , in the sera and lesional skin was reported in patients with erythrodermic CTCL ( 10 ). Serum levels of angiopoietin-2 ( Ang-2 ), which has the capacity to promote both angiogenesis and lymphangiogenesis , are also elevated in patients with SS and are correlated with disease severity markers ( 11 ).
Among pro-angiogenic and pro-lymphangiogenic factors , vascular endothelial growth factor ( VEGF ) family is generally regarded as the key player in both physiological and pathological skin angiogenesis and lymphangiogenesis . VEGF family comprises VEGF-A , VEGF-B , VEGF-C , VEGF-D , and placental growth factor ( PlGF ). VEGF-A activates VEGF receptor ( VEGFR ) -1 and VEGFR-2 on vascular endothelial cells and promotes angiogenesis . VEGF-B and PlGF bind to VEGFR-1 and manifest angiogenic properties . VEGF-C and VEGF-D mainly modulate lymphangiogenesis through VEGFR-3 , but may also induce angiogenesis through VEGFR-2 . VEGF-A is secreted by tumour cells of MF and cell lines of MF / SS , while its receptors , VEGFR-1 and VEGFR-2 , are not expressed on tumour cells ( 12 – 14 ). Thus , VEGF-A may contribute to MF / SS progression through angiogenesis . However , PlGF involvement in MF / SS has not been studied , whereas PlGF is known to have strong angiogenic properties in the skin , partially via enhancing VEGF-A action ( 15 , 16 ).
The aim of this study was to measure the expression of both PlGF and VEGF-A in lesional skin and PlGF expression in sera of patients with MF / SS . A further aim was to assess the effects of PlGF on lymphoma cell growth in vivo to clarify the involvement of PlGF in the development of MF / SS . doi : 10.2340 / 00015555-2623 Acta Derm Venereol 2017 ; 97 : 586 – 592
This is an open access article under the CC BY-NC license . www . medicaljournals . se / acta Journal Compilation © 2017 Acta Dermato-Venereologica .