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Chapter 4
MOLECULAR MECHANISMS OF LYMPH
NODE METASTASIS
Matthias Rinderknecht and Michael Detmar
Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH
Zurich, CH-8093 Zurich, Switzerland, e-mail: michael.detmar@pharma.ethz.ch
Abstract: Lymph node metastasis represents the first step of spread for most hu-
man cancers and serves as an important prognostic indicator. Recent
studies have revealed that tumors can actively induce the growth of
tumor-associated lymphatic vessels (lymphangiogenesis), thus promot-
ing their metastasis to draining (sentinel) lymph nodes. Several tumor
lymphangiogenesis factors have been identified, including vascular en-
dothelial growth factor (VEGF)-C, VEGF-D, VEGF-A and hepatocyte
growth factor. A large number of clinical studies have confirmed the
correlation of tumor lymphangiogenesis and metastasis of different
types of human cancers. Importantly, recent results indicate that tumors
can also induce lymphatic vessel growth in sentinel lymph nodes, even
before the onset of metastasis, and that lymph node lymphangiogenesis
further promotes cancer spread to distant lymph nodes and to distant
organs. Thus, in addition to its prognostic importance, lymphangiogen-
esis has become a new target for the prevention, treatment and imaging
of lymph node metastases.
Key words: Cancer · Lymphangiogenesis · Lymphatic metastasis · VEGF-A ·
VEGF-C · VEGFR-3
4.1 Introduction to the Lymphatic System
The lymphatic vascular system was first described in the 17th century by the Ital-
ian surgeon and anatomist Gasparo Aselli [6]. He described the lacteal lymphatic
vessels, conveying milky-white chyle, as “milky veins” in the intestine of a dog.
Lat
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