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Lymphangiogenesis and Tumor Metastasis: Myth Or Reality?1

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Lymphangiogenesis and Tumor Metastasis: Myth Or Reality?1 462 Vol. 7, 462–468, March 2001 Clinical Cancer Research Minireview Lymphangiogenesis and Tumor Metastasis: Myth or Reality?1 Michael S. Pepper2 lymphatics is the most common pathway of initial dissemina- Department of Morphology, University Medical Center, 1211 Geneva tion, with patterns of spread via afferent lymphatics following 4, Switzerland 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- Abstract tasize to these lymph nodes, although intralymphatic tumor cells The metastatic spread of tumor cells is responsible for can pass directly into the blood vascular system through the majority of cancer deaths, and with few exceptions, all venolymphatic communications, and vice versa. Sentinel lymph cancers can metastasize. Clinical findings have long sug- node biopsy and histopathological examination improve tumor gested that by providing a pathway for tumor cell dissemi- staging and facilitate the planning of therapeutic strategies (re- nation, tumor-associated lymphatics are a key component of viewed in Refs. 1–3). metastatic spread. It is not known, however, whether pre- Despite these well-established principles, many key ques- existing vessels are sufficient to serve this function, or tions regarding the mechanisms of lymphatic tumor spread still whether tumor cell dissemination requires de novo lym- remain unanswered: phatic formation (lymphangiogenesis) or an increase in lym- (a) Does the de novo formation of lymphatic capillaries phatic size. Lymphangiogenesis has traditionally been over- (lymphangiogenesis) and/or lymphatic enlargement dilatation shadowed by the greater emphasis placed on the blood increase the probability of lymphatic tumor dissemination be- vascular system (angiogenesis). This is due in part to the lack yond that which would occur exclusively through preexisting of identification of lymphangiogenic factors, as well as suit- vessels? able markers that distinguish blood from lymphatic vascu- (b) What are the molecular mechanisms of lymphangio- lar endothelium. This scenario is changing rapidly after the genesis and lymphatic enlargement? identification of the first lymphangiogenic factor, vascular (c) Is the process of tumor cell intravasation into lymphat- endothelial growth factor C (VEGF-C). Increased expres- ics analogous to that which occurs in the blood vascular system? sion of VEGF-C in primary tumors correlates with in- (d) Is inhibition of lymphangiogenesis a realistic therapeu- creased dissemination of tumor cells to regional lymph tic strategy for inhibiting tumor cell dissemination and the nodes in a variety of human carcinomas. Here I will review formation of metastasis? what is known about the mechanisms of lymphangiogenesis, It has long been suggested that “A lymphatic system as an particularly in the context of metastatic tumor spread, and anatomical entity is not demonstrable in tumors” (4), and studies will critically examine the role of VEGF-C in this process. in human and animal tumors involving injection of tracers into However, despite recent progress in this field, it remains to lymphatics revealed that tumors do not have an intrinsic lym- be determined whether inhibition of lymphangiogenesis is a phatic vascular supply (see, for example, Refs. 5 and 6). How- realistic therapeutic strategy for inhibiting tumor cell dis- ever, it has been proposed that this reflects the collapse of semination and the formation of metastasis. lymphatics within the tumor due to mechanical stress generated by proliferating cancer cells, and that this in turn contributes to Introduction increased pressure within the tumor interstitium (7). Although With few exceptions, all cancers can metastasize. Metas- the lack of intratumoral lymphatics appears to be a consistent tasis unequivocally signifies that a tumor is malignant, and the feature, dilated and engorged lymphatics in peritumoral stroma, metastatic spread of tumor cells is responsible for the majority which occasionally penetrate into the tumor periphery, are fea- of cancer deaths. Tumor dissemination may occur through a tures that are observed with equal frequency (7, 8). It has been number of pathways: (a) local tissue invasion; (b) direct seeding suggested that these lymphatics are likely to be existing lym- 3 of body cavities or surfaces; (c) hematogenous spread; and (d) phatics that have enlarged in response to VEGF-C , rather than lymphatic spread. Clinical and pathological observations sug- new lymphatic vessels (lymphangiogenesis; Ref. 7). gest that for many carcinomas, transport of tumor cells via 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- Received 11/2/00; revised 12/13/00; accepted 12/28/00. ence of an open lymphatic labyrinth in close association with the The costs of publication of this article were defrayed in part by the primary tumor and suggests that “Tumor cells lying free in 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 3 The abbreviations used are: VEGF, vascular endothelial growth factor; Gene`ve 4, Switzerland. Phone: 4122-702-52-91; Fax: 4122-347-33-34; VEGFR, VEGF receptor; bFGF, basic fibroblast growth factor; TNF, E-mail: [email protected]. tumor necrosis factor. Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2001 American Association for Cancer Research. Clinical Cancer Research 463 periductal lymphatic spaces will be washed with the tide of ency to retract or undergo changes in size or form. Although tissue fluid into the labyrinth through the sinuses and on into the temporary lymphedema occurs after lymphatic disruption, this lymphatic drainage channels. There is no need to postulate usually resolves due to spontaneous regeneration or reconnec- active lymphatic invasion.” Evidence in favor of this hypothesis tion of lymphatics (18–20). Therefore, despite microsurgical or the alternative hypothesis of active tumor cell intravasation is advances in the repair of severed arteries, veins, and nerves, still lacking in the lymphatic system. disrupted lymphatics are usually not identified or reconnected during surgical intervention. In a study on incisional and punch biopsy skin wounds, Paavonen et al. (21) have confirmed that Mechanisms of Lymphangiogenesis in Vivo new lymphatic vessels appear a few days after blood vessels in Before considering the mechanisms of lymphangiogenesis, the peripheral granulation tissue. They also found that in resolv- it is necessary to recall the morphological features that distin- ing inflammation at the end of the wound-healing process, guish lymphatic capillaries from capillaries of the blood vascu- lymphatic capillaries tended to involute more rapidly than blood lar system. Like the latter, lymphatic capillaries are lined by a capillaries. Extensive lymphatic proliferation has also been ob- single layer of endothelial cells. However, unlike blood capil- served in acute and chronic inflammation outside of the wound- lary endothelium, lymphatic endothelial cells have poorly de- healing process (22). Newly formed lymphatics regress on res- veloped junctions with frequent large interendothelial gaps. olution of the inflammatory process. Lymphatic endothelial cells are also devoid of fenestrations. Lymphangiogenesis has traditionally been overshadowed Because pressure within lymphatic capillaries is only slightly by the greater emphasis placed on the blood vascular system higher than the interstitium, lumen patency is maintained by (angiogenesis). This is due in part to the lack of identification of anchoring filaments that connect the abluminal surfaces of en- lymphangiogenic factors, as well as suitable markers with which dothelial cells to the perivascular extracellular matrix. In con- to distinguish blood from lymphatic vascular endothelium. trast to capillary blood vessels, lymphatic capillaries do not However, this scenario is changing rapidly following the dis- possess a continuous basement membrane, and they are devoid covery of the first lymphangiogenic factor, VEGF-C (23, 24). of pericytes. However, like blood vascular endothelium, lym- phatic endothelial cells contain Weibel-Palade bodies, and they are immunoreactive for von Willebrand factor and CD31 (plate- VEGF-C let/endothelial cell adhesion molecule 1). VEGF-C is a member of the VEGF family of growth During early development of the blood vascular system factors, which are highly conserved secreted glycoproteins that (vasculogenesis), new capillaries arise either de novo from regulate vasculogenesis, hematopoiesis, angiogenesis, lym- mesoderm-derived angioblasts or by sprouting from newly phangiogenesis, and vascular permeability and are implicated in formed vessels. How do new lymphatic capillaries arise during many physiological and pathological processes. To date, the embryogenesis? Studies on lymphatic ontogeny performed al- VEGF family is comprised of VEGF-A, -B, -C, and
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