Arkadiusz Z. Dudek

Kalpna Gupta

Sundaram Ramakrishnan

Debabrata Mukhopadhyay

Tumor Angiogenesis 2012

Metastasis the spread of cancer cells to distant organs, is the main cause of death for cancer patients. Metastasis is often mediated by lymphatic vessels that invade the primary tumor, and an early sign of metastasis is the presence of cancer cells in the regional lymph node (the first lymph node colonized by metastasizing cancer cells from a primary tumor). Understanding the interplay between tumorigenesis and lymphangiogenesis (the formation of lymphatic vessels associated with tumor growth) will provide us with new insights into mechanisms that modulate metastatic spread. In the long term, these insights will help to define new molecular targets that could be used to block lymphatic vessel-mediated metastasis and increase patient survival. Here, we review the molecular mechanisms of embryonic lymphangiogenesis and those that are recapitulated in tumor lymphangiogenesis, with a view to identifying potential targets for therapies designed to suppress tumor lymphangiogenesis and hence metastasis.

Tam Duong

Peter Koopman

Mathias Francois

Tumor Lymphangiogenesis as a Potential Therapeutic Target

Morphine stimulates tumor angiogenesis and cancer progression in mice. We examined if morphine influences endothelial-pericyte interaction via platelet-derived growth factor-BB (PDGF-BB) and PDGF receptor-<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>β</mml:mi></mml:math> (PDGFR-<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>β</mml:mi></mml:math>). Clinically relevant doses of morphine stimulated PDGF-BB secretion from human umbilical vein endothelial cells and activated PDGFR-<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>β</mml:mi></mml:math> and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) phosphorylation in human pericytes. These in vitro effects of morphine were translated into promotion of tumor angiogenesis in a transgenic mice model of breast cancer when treated with clinically used dose of morphine. Increased vessel-associated immunoreactivity of desmin and PDGFR-<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>β</mml:mi></mml:math> was observed on pericytes in tumors of morphine-treated mice. These data suggest that morphine potentiates endothelial-pericyte interaction via PDGF-BB/PDGFR-<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>β</mml:mi></mml:math> signaling and promotes tumor angiogenesis, pericyte recruitment, and coverage of tumor vessels. We speculate that morphine may impair the effectiveness of antiangiogenic therapy by influencing vascular pericyte coverage.

Kathryn Luk

Sonja Boatman

Katherine N. Johnson

Olivia A. Dudek

Natalie Ristau

Derek Vang

Julia Nguyen

Influence of Morphine on Pericyte-Endothelial Interaction: Implications for Antiangiogenic Therapy

Our previous studies demonstrated arsenic trioxide- (ATO-) induced selective tumor vascular disruption and augmentation of thermal or radiotherapy effect against solid tumors. These results suggested that a trimodality approach of radiation, ATO, and local hyperthermia may have potent therapeutic efficacy against solid tumors. Here, we report the antitumor effect of hypofractionated radiation followed by ATO administration and local 42.5 °C hyperthermia and the effects of cisplatin and thermoradiotherapy. We found that the therapeutic efficacy of ATO-based thermoradiotherapy was equal or greater than that of cisplatin-based thermoradiotherapy, and marked evidence of in vivo apoptosis and tumor necrosis were observed in ATO-treated tumors. We conclude that ATO-based thermoradiotherapy is a powerful means to control tumor growth by using vascular disruption to augment the effects of thermal and radiation therapy.

Robert J. Griffin

Brent W. Williams

Nathan A. Koonce

John C. Bischof

Chang W. Song

Rajalakshmi Asur

Meenakshi Upreti

Vascular Disrupting Agent Arsenic Trioxide Enhances Thermoradiotherapy of Solid Tumors

Mature vasculature contains an endothelial cell lining with a surrounding sheath of pericytes/vascular smooth muscle cells (VSMCs). Tumor vessels are immature and lack a pericyte sheath. Colocalization of vascular endothelial growth factor receptor 2 (VEGFR-2) and platelet-derived growth factor receptor beta (PDGF-Rβ) reduces pericyte ensheathment of tumor vessels. We found that a 30% dietary restriction (DR) enhanced vessel maturation in the mouse CT-2A astrocytoma. DR reduced microvessel density and VEGF expression in the astrocytoma, while increasing recruitment of pericytes, positive for alpha-smooth muscle actin (α-SMA). Moreover, DR reduced colocalization of VEGF-R2 and PDGF-Rβ, but did not reduce total PDGF-Rβ expression. These findings suggest that DR promoted vessel normalization by preventing VEGF-induced inhibition of the PDGF signaling axis in pericytes. DR appears to shift the tumor vasculature from a leaky immature state to a more mature state. We suggest that vessel normalization could improve delivery of therapeutic drugs to brain tumors.

Ivan Urits

Purna Mukherjee

Joshua Meidenbauer

Thomas N. Seyfried

Dietary Restriction Promotes Vessel Maturation in a Mouse Astrocytoma

Much has been learned about the mechanisms underlying tumor angiogenesis, and therapies that target vascular endothelial growth factor (VEGF) to limit tumor angiogenesis and subsequent disease progression have recently been approved. However, the transcriptional mechanisms that regulate pathological angiogenesis remain largely unknown. FoxC2, a member of the Forkhead box (Fox) transcription factor family, is critical for vascular formation during development, and recent studies have shown that FoxC2 is expressed in the endothelium of tumors in both humans and mice. In a B16 mouse melanoma model, Foxc2 deficiency reduced tumor growth and neovascularization and was associated with impairments in mural-cell coverage and increases in endothelial-cell apoptosis in tumor blood vessels. FoxC2 is also expressed by tumor cells in human breast, colonic, and esophageal cancer and participates in the epithelial-mesenchymal transition (EMT), a key process that leads to the invasion and metastasis of aggressive tumors. Collectively, these observations suggest that FoxC2 is essential for tumor angiogenesis and disease progression and that FoxC2 may be a viable target for cancer therapy.

Tsutomu Kume

The Role of FoxC2 Transcription Factor in Tumor Angiogenesis

Angiogenesis is a necessary process for tumor growth, progression and diffusion. In the last years
many efforts have been made to understand the mechanisms necessary to the formation of new
vessels in tumor tissue and how to integrate these findings in the treatment of different type of
cancer. Thanks to these studies there are today many anti-angiogenic drugs with established
activity in cancer and approved in clinical practice.
Head and neck cancer is a common tumor worldwide that often has advanced stage at diagnosis and
poor prognosis. Angiogenesis has a well recognized role in head and neck cancer progression and
resistance to drugs and radiotherapy and many clinical trials has been conducted with antiangiogenic
agents in this disease, even if they often showed limited efficacy.
In this review we summarize the main trials published about angiogenesis in head and neck cancer
with particular attention to factors involved in this process and the available data on the efficacy of
treatment with anti-angiogenic agents in this disease.

Codec&#224; Carla

Ferrari Daris

Bertuzzi Cecilia

Broggio Francesca

Crepaldi Francesca

Foa Paolo

Angiogenesis in Head and Neck Cancer: A Review of the Literature

In vivo real-time visualization of the process of angiogenesis in secondary tumors in the same living animals presents a major challenge in metastasis research. We developed a technique for intravital imaging of colorectal liver metastasis development in live mice using two-photon laser scanning microscopy (TPLSM). We also developed time-series TPLSM in which intravital TPLSM procedures were performed several times over periods of days to months. Red fluorescent protein-expressing colorectal cancer cells were inoculated into the spleens of green fluorescent protein-expressing mice. First- and second-round intravital TPLSM allowed visualization of viable cancer cells (red) in hepatic sinusoids or the space of Disse. Third-round intravital TPLSM demonstrated liver metastatic colonies consisting of viable cancer cells and surrounding stroma with tumor vessels (green). In vivo time-course imaging of tumor angiogenesis in the same living mice using time-series TPLSM could be an ideal tool for antiangiogenic drug evaluation, reducing the effects of interindividual variation.

Koji Tanaka

Yuhki Morimoto

Yuji Toiyama

Kohei Matsushita

Mikio Kawamura

Yuhki Koike

Yoshinaga Okugawa

Yasuhiro Inoue

Keiichi Uchida

Toshimitsu Araki

Akira Mizoguchi

Masato Kusunoki

In Vivo Time-Course Imaging of Tumor Angiogenesis in Colorectal Liver Metastases in the Same Living Mice Using Two-Photon Laser Scanning Microscopy

Angiogenesis, an essential component of tumor growth and survival, is regulated by complex interactions between several cell types and soluble mediators. Heterogeneous tumor vasculature originates from the collective effect of the nature of carcinoma and the complexity of the angiogenic network. Although the application of angiogenesis inhibitors in some types of cancers has shown clinical benefits, predictive markers to assess treatment effects have yet to be established. In this review, we focus on tumor vessel maturity as a potential marker for evaluating treatment response.

Elham Fakhrejahani

Masakazu Toi

Tumor Angiogenesis: Pericytes and Maturation Are Not to Be Ignored

Antiangiogenic therapy is theoretically a promising anticancer approach but does not always produce significant tumor control. Combinations of antiangiogenic therapies are therefore being investigated as strategies to enhance clinical benefit. Common targets for angiogenic blockade include endothelial specific receptors, such as Tie2/Tek, which signal blood vessel stabilization via recruitment and maturation of pericytes. Here, we report on the effects of targeted Tie2 antiangiogenic therapy (TekdeltaFc) in combination with nontargeted metronomic cyclophosphamide (LDM CTX) (reported to also act in antiangiogenic fashion) in xenografted human melanoma. Individually, these therapies showed transient antitumor activity, but, in combination, there was no significant reduction in tumor growth. In addition, while TekdeltaFc caused the expected increased pericyte coverage in treated blood vessels, LDM CTX alone or in combination with TekdeltaFc resulted in increased levels of VEGF production. Collectively, our data highlight the complexity of molecular interactions that may take place when antiangiogenic regimens are combined.

Una Adamcic

Clorinda Castagna

Kanwal Minhas

Siranoush Shahrzad

Brenda L. Coomber

Lack of Efficacy of Combined Antiangiogenic Therapies in Xenografted Human Melanoma

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Journal of Oncology publishes research related to breast cancer, lung cancer, gastrointestinal cancer, skin cancer, head and neck cancer, paediatric oncology, neurooncology as well as genitourinary cancer.

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Chief Editor, Professor Bruno Vincenzi, is an Associate Professor of Medical Oncology at University Campus Bio-Medico, Italy. His research interests include urogenital neoplasms and the pathophysiology and treatment of bone metastases.

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Journal of Oncology

Tumor Angiogenesis 2012

Tumor Angiogenesis 2012

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