Minireview Lymphangiogenesis and Tumor Metastasis: Myth or Reality? 1 Michael S. Pepper 2 Department of Morphology, University Medical Center, 1211 Geneva 4, Switzerland Abstract The metastatic spread of tumor cells is responsible for the majority of cancer deaths, and with few exceptions, all cancers can metastasize. Clinical findings have long sug- gested that by providing a pathway for tumor cell dissemi- nation, tumor-associated lymphatics are a key component of metastatic spread. It is not known, however, whether pre- existing vessels are sufficient to serve this function, or whether tumor cell dissemination requires de novo lym- phatic formation (lymphangiogenesis) or an increase in lym- phatic size. Lymphangiogenesis has traditionally been over- shadowed by the greater emphasis placed on the blood vascular system (angiogenesis). This is due in part to the lack of identification of lymphangiogenic factors, as well as suit- able markers that distinguish blood from lymphatic vascu- lar endothelium. This scenario is changing rapidly after the identification of the first lymphangiogenic factor, vascular endothelial growth factor C (VEGF-C). Increased expres- sion of VEGF-C in primary tumors correlates with in- creased dissemination of tumor cells to regional lymph nodes in a variety of human carcinomas. Here I will review what is known about the mechanisms of lymphangiogenesis, particularly in the context of metastatic tumor spread, and will critically examine the role of VEGF-C in this process. However, despite recent progress in this field, it remains to be determined whether inhibition of lymphangiogenesis is a realistic therapeutic strategy for inhibiting tumor cell dis- semination and the formation of metastasis. Introduction With few exceptions, all cancers can metastasize. Metas- tasis unequivocally signifies that a tumor is malignant, and the metastatic spread of tumor cells is responsible for the majority of cancer deaths. Tumor dissemination may occur through a number of pathways: (a) local tissue invasion; (b) direct seeding of body cavities or surfaces; (c) hematogenous spread; and (d) lymphatic spread. Clinical and pathological observations sug- gest that for many carcinomas, transport of tumor cells via lymphatics is the most common pathway of initial dissemina- tion, with patterns of spread via afferent lymphatics following routes of natural drainage. Sentinel lymph nodes are a variable but limited set of nodes that are the first to receive drainage from any given location. As a rule, carcinomas preferentially metas- tasize to these lymph nodes, although intralymphatic tumor cells can pass directly into the blood vascular system through venolymphatic communications, and vice versa. Sentinel lymph node biopsy and histopathological examination improve tumor staging and facilitate the planning of therapeutic strategies (re- viewed in Refs. 1–3). Despite these well-established principles, many key ques- tions regarding the mechanisms of lymphatic tumor spread still remain unanswered: (a) Does the de novo formation of lymphatic capillaries (lymphangiogenesis) and/or lymphatic enlargement dilatation increase the probability of lymphatic tumor dissemination be- yond that which would occur exclusively through preexisting vessels? (b) What are the molecular mechanisms of lymphangio- genesis and lymphatic enlargement? (c) Is the process of tumor cell intravasation into lymphat- ics analogous to that which occurs in the blood vascular system? (d) Is inhibition of lymphangiogenesis a realistic therapeu- tic strategy for inhibiting tumor cell dissemination and the formation of metastasis? It has long been suggested that “A lymphatic system as an anatomical entity is not demonstrable in tumors” (4), and studies in human and animal tumors involving injection of tracers into lymphatics revealed that tumors do not have an intrinsic lym- phatic vascular supply (see, for example, Refs. 5 and 6). How- ever, it has been proposed that this reflects the collapse of lymphatics within the tumor due to mechanical stress generated by proliferating cancer cells, and that this in turn contributes to increased pressure within the tumor interstitium (7). Although the lack of intratumoral lymphatics appears to be a consistent feature, dilated and engorged lymphatics in peritumoral stroma, which occasionally penetrate into the tumor periphery, are fea- tures that are observed with equal frequency (7, 8). It has been suggested that these lymphatics are likely to be existing lym- phatics that have enlarged in response to VEGF-C 3 , rather than new lymphatic vessels (lymphangiogenesis; Ref. 7). The presence of tumor cells in peri- or juxtatumoral lym- phatics is not an uncommon feature for many primary tumors. Does lymphatic dissemination of tumor cells require active tumor cell intravasation into lymphatic vessels? In a detailed study on breast carcinoma, Hartveit (8) has described the pres- ence of an open lymphatic labyrinth in close association with the primary tumor and suggests that “Tumor cells lying free in the Received 11/2/00; revised 12/13/00; accepted 12/28/00. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 Supported by grants from the Swiss National Science Foundation. 2 To whom requests for reprints should be addressed, at Department of Morphology, University Medical Center, 1 rue Michel Servet, 1211 Gene `ve 4, Switzerland. Phone: 4122-702-52-91; Fax: 4122-347-33-34; E-mail: michael.pepper@medecine.unige.ch. 3 The abbreviations used are: VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor; bFGF, basic fibroblast growth factor; TNF, tumor necrosis factor. 462 Vol. 7, 462– 468, March 2001 Clinical Cancer Research Research. on November 24, 2021. © 2001 American Association for Cancer clincancerres.aacrjournals.org Downloaded from