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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.