COMMENTARY

Intratumoral Lymphatic Vessels: A Case of Mistaken Identity or Malfunction?

Rakesh K. Jain, Brenda T. Fenton

Affiliation of authors: Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA.

Correspondence to: Rakesh K. Jain, Ph.D., Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, 100 Blossom Street, Cox-7, Boston, MA 02114 (e-mail: jain{at}steele.mgh.harvard.edu).

Metastasis is the major cause of mortality from malignant tumors. Metastatic cancer cells spread to various organs via the vascular system (hematogenic metastasis) and/or the lymphatic system (lymphogenic metastasis). Compared with our understanding of a tumor's vascular system, our understanding of its lymphatic system is minimal, although it has been known for some time that lymphatic vessels are present in the margins of animal and human tumors. Indeed, invasion of peritumor lymphatics is considered to be a poor prognostic factor for patients with some tumors (e.g., breast, colorectal, and endometrial cancers), and lymphatic metastasis is a major cause of morbidity and mortality for others (e.g., melanoma, head and neck, lung, and cervical cancers; www.uptodate.com). For nearly a century, it has been a hotly debated issue whether anatomically defined lymphatic vessels are present within solid tumors (1) and, if so, whether they function (2) (Fig. 1Go). However, the discovery of two lymphangiogenic molecules, vascular endothelial growth factor (VEGF)-C and VEGF-D, and their receptor VEGFR3 changed the landscape for lymphatic studies by providing the critical molecular players and tools (3). A series of recent reports (48) suggests that overexpression of VEGF-C or -D is associated with lymphangiogenesis in tumors and with increased lymphatic metastasis in mice. Despite the aforementioned studies (48), many questions remain regarding the molecular mechanisms of lymphangiogenesis, the specificity of growth factors and lymphatic markers, and the ability of lymphatics to function within tumors.



View larger version (149K):
[in this window]
[in a new window]
 
Fig. 1. Schematic of a tumor showing our current understanding of the lymphatic system in tumors expressing low levels (left) versus high levels (right) of vascular endothelial growth factor (VEGF)-C and VEGF-D. Note that engorged lymphatic vessels are present in the tumor margin and the peritumor tissue. VEGF-C/D may increase the diameter and number of these lymphatic vessels, thus providing increased surface area to facilitate lymphatic metastasis. Currently available immunohistochemical markers can be used to stain for structures within some tumors that resemble lymphatic vessels. However, because many of these markers lack specificity, it is not clear whether they stain functional lymphatic vessels, endothelial cells from remnant lymphatic vessels, or some other structures (e.g., preferential fluid channels in the extracellular matrix). The stress induced by proliferating cancer cells may compress and impair lymphatic vessels that are coopted or formed in the tumor. The impaired lymphatic vessels, in turn, may contribute to the interstitial hypertension characteristic of animal and human tumors. The left-bottom inset shows some of the known molecular players in lymphangiogenesis: endothelial cell receptors = vascular endothelial growth factor receptor 3 (VEGFR-3), neuropilin-2 (NRP-2), and Tie-2; receptor ligands = VEGF-C and VEGF-D and angiopoietin-2 (Ang-2). The remaining insets each show a magnified schematic of the region indicated (not drawn to scale).

 
What molecular mechanisms are involved in lymphangiogenesis in tumors? VEGF-C or VEGF-D can induce lymphangiogenesis via the activation of signaling pathways through VEGFR3 on lymphatic endothelial cells (3) and are associated with lymphogenic metastasis in a variety of tumors (Table 1Go). However, they can also increase vascular angiogenesis (4,8,9) and increase distant metastasis in some tumors (5), indicating that they lack specificity for lymphatic vessels. Like vascular angiogenesis, other positive and negative regulators, such as angiopoietins (10), and other receptors, such as {beta}-chemokine receptor D6 and neuropilin-2 (11), may be involved in lymphangiogenesis, and mechanisms analogous to cooption, intussusception, sprouting, and vasculogenesis may operate in lymphatic growth (12). Similar to the recently discovered organ-specific angiogenic molecule (EG-VEGF) (13) and endothelial precursor cells (14), there may be organ-specific lymphangiogenic molecules and lymphatic endothelial precursor cells that contribute to tumor-associated lymphangiogenesis. Moreover, the proteolytic processing of lymphangiogenic molecules as well as the phenotype and function of the resulting lymphatics may depend not only on the tumor type but also on the host organ in which the tumor is growing (3,8,9).


View this table:
[in this window]
[in a new window]
 
Table 1. Association between VEGF-C or VEGF-D with clinicopathologic endpoints*
 
A more fundamental question that remains unanswered is what molecular and/or mechanical signals trigger the lymphangiogenic switch. For vascular angiogenesis, triggers include metabolic stress (e.g., low pO2 and/or low pH), mechanical stress (e.g., shear stress), immune/inflammatory responses, and/or genetic mutations in the cancer cells (12). Because lymphatic vessels maintain the balance of fluid in tissues, hydrostatic pressure may be a likely trigger for lymphangiogenesis. Tumors are known to have elevated hydrostatic pressure (15). Whether the hyperplasia seen in the tumor margins is a response to this trigger and whether the resulting lymphatics can remain open inside a solid tumor under the stress generated by proliferating cancer cells are open questions (2,16,17).

Answering questions about the formation and function of tumor-associated lymphatic vessels would require specific markers for the identification of endothelial cells from lymphatic capillaries and techniques that can discern lymphatic function microscopically. Both specific markers and appropriate techniques have been a challenge to develop. Initially, the expression of VEGFR3, a receptor for VEGF-C and VEGF-D, was considered to be restricted to the adult lymphatic endothelium. However, expression of VEGFR3 was later found to be present in the fenestrated (with window-like openings) blood vessels of normal tissues and in the angiogenic blood vessels of the retina, of wounds, and of tumors (1820). Thus, VEGFR3 is not considered a specific marker for lymphatic vessels. Consequently, although several investigators have identified VEGFR3-positive vessels within animal (2) and human (18) tumors, the fraction of these vessels that are lymphatic vessels could not be ascertained. Nevertheless, antibodies against VEGFR3 and podoplanin, another lymphatic marker (21), have been useful in the isolation of lymphatic endothelial cells (22,23) and in extending previous work on harvesting and characterizing these cells (2426).

Further progress in the markers for the identification of lymphatic vessels came with the discovery of lymphatic vessel endothelial hyaluronan receptor (LYVE)-1, a hyaluronan receptor on lymphatic endothelial cells (27). In immunohistochemical analyses, polyclonal antibodies against LYVE-1 stained lymphatics but not blood vessels in a number of normal murine and human tissues (28), potentially overcoming some of the problems associated with VEGFR3. However, the recent discovery that LYVE-1 is expressed by the blood sinusoids of murine and human liver, a major organ for hyaluronan catabolism, suggests that the story may be more complex (29). Clearly, additional lymphatic-specific markers and functional studies are needed.

An additional candidate lymphatic marker is the homeobox protein Prox 1, a nuclear transcription factor required for embryonic lymphangiogenesis (30). Prox 1 is present in lymphatic, but not vascular, endothelial cells of various normal adult tissues, and unlike LYVE-1, Prox 1 does not stain normal liver sinusoids (29). It is also present in VEGF-C overexpressing human tumors xenografted on the chicken chorioallantoic membrane (31). However, because Prox 1 is a nuclear protein that is also present in a number of nonendothelial cells, its specificity of expression for lymphatic vessels must be determined in conjunction with another cytoplasmic or membrane marker, such as LYVE-1. The combination of Prox 1 and LYVE-1 might provide the much sought after specificity for the identification of lymphatic vessels (29). However, given the plasticity of tumor vessels, functional studies that measure fluid transport, macromolecular transport, and/or cell transport in Prox 1 and LYVE-1 double-positive vessels in tumors are needed to test this hypothesis.

Interestingly, patients with hepatocellular or metastatic colorectal carcinomas were found to have LYVE-1 and Prox 1 double-positive vessels—presumably lymphatic vessels—only in the periphery of their tumors (29). The lack of lymphatics inside primary and secondary human liver tumors is consistent with previous results (32), along with the recent findings in murine fibrosarcomas grown orthotopically in the mouse tail (using lymphangiography) (2) and in spontaneously arising pancreatic tumors in RIP-Tag/VEGF-C transgenic mice (using LYVE-1) (6). The latter study also showed an increase in lymphatic metastasis without intratumor lymphangiogenesis (6).

The finding that lymphatic metastasis increased in the absence of intratumor lymphatics raises an interesting question: Is intratumor lymphangiogenesis necessary for increased metastasis? The answer is: maybe not. Two recent studies (4,5) showed an association between intratumor LYVE-1-positive vessels in VEGF-C/D overexpressing tumors and the number of lymph node metastases. It is likely that a similar association would exist between lymphatic vessels in the tumor margin and metastases, but this possibility was not evaluated. There is strong evidence that the lymphatic system is functionally impaired in tumors with respect to fluid and macromolecular transport (2). This impairment contributes to interstitial hypertension, a pathophysiologic characteristic of animal and human tumors (15). Moreover, the interstitial pressure is relatively uniform throughout the tumor, suggesting a paucity of sinks (i.e., functional lymphatic vessels) for fluid uptake. Whether cancer cells can use impaired intratumor lymphatic vessels or the preferential fluid channels reported in some tumors (1,33) to metastasize to the nearby lymph nodes is unknown. Functional studies are needed to address this important question in experimental and human cancers. Techniques such as microlymphangiography, wherein a fluorescent macromolecule is injected into the tissue, picked up by lymphatic capillaries and detected by microscopy, have been developed and used to examine lymphatic function in mice (2,3438). Furthermore, with the increasing availability of small (e.g., kinase inhibitors) and large molecules (e.g., peptides, antibodies, soluble receptors) that interfere with the signaling of VEGFR3 and other lymphatic endothelial cell receptors, the causal relationship between the function of VEGF-C and VEGF-D, as well as other lymphangiogenic factors yet to be discovered, and metastasis will begin to be discerned. An improved understanding of the formation and the function of tumor-associated lymphatic vessels would facilitate not only the potential control of metastasis but also the delivery of therapeutic agents to tumors. In the meantime, regardless of their specificity, the recently identified molecular markers (e.g., LYVE-1, Prox 1, podoplanin) may serve as useful prognostic indicators for some cancers.

NOTES

Supported by a Bioengineering Research Partnership Grant (R24-CA-85140) and a Training Grant (T32-CA-73479) from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services.

We thank Timothy Padera, Yves Boucher, Emmanuelle diTomaso, and Christopher Willett for their critical input and Lance Munn for his artwork.

REFERENCES

1 Gullino PM. Extracellular compartments of solid tumors. In: Becker, FF, editor. Cancer. Vol. 3. New York (NY): Plenum; 1975. p. 327–54.

2 Leu AJ, Berk DA, Lymboussaki A, Alitalo K, Jain RK. Absence of functional lymphatics within a murine sarcoma: a molecular and functional evaluation. Cancer Res 2000;60:4324–7.[Abstract/Free Full Text]

3 Karpanen T, Alitalo K. Lymphatic vessels as targets for tumor therapy? J Exp Med 2001;194:F37–42.[Free Full Text]

4 Stacker SA, Caesar C, Baldwin ME, Thornton GE, Williams RA, Prevo R, et al. VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nat Med 2001;7:186–91.[Medline]

5 Skobe M, Hawighorst T, Jackson DG, Prevo R, Janes L, Velasco P, et al. Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nat Med 2001;7:192–8.[Medline]

6 Mandriota SJ, Jussila L, Jeltsch M, Compagni A, Baetens D, Prevo R, et al. Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumor metastasis. EMBO J 2001;20:672–82.[Abstract/Free Full Text]

7 Karpanen T, Egeblad M, Karkkainen MJ, Kubo H, Yla-Herttuala S, Jaattela M, et al. Vascular endothelial growth factor C promotes tumor lymphangiogenesis and intralymphatic tumor growth. Cancer Res 2001;61:1786–90.[Abstract/Free Full Text]

8 Skobe M, Hamberg LM, Hawighorst T, Schirner M, Wolf GL, Alitalo K, et al. Concurrent induction of lymphangiogenesis, angiogenesis, and macrophage recruitment by vascular endothelial growth factor-C in melanoma. Am J Path 2001;159:893–903.[Abstract/Free Full Text]

9 Kadambi A, Carreira CM, Yun CO, Padera TP, Dolmans DE, Carmeliet P, et al. Vascular endothelial growth factor (VEGF)-C differentially affects tumor vascular function and leukocyte recruitment: role of VEGF-Receptor 2 and host VEGF-A. Cancer Res 2001;61:2404–8.[Abstract/Free Full Text]

10 Yancopoulos GD, Davis S, Gale NW, Rudge JS, Wiegand SJ, Holash J. Vascular-specific growth factors and blood vessel formation. Nature 2000;407:242–8.[Medline]

11 Karkkainen MJ, Saaristo A, Jussila L, Karila KA, Lawrence EC, Pajusola K, et al. A model for gene therapy of human hereditary lymphedema. Proc Natl Acad Sci U S A 2001;98:12677–82.[Abstract/Free Full Text]

12 Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature 2000;407:249–57.[Medline]

13 LeCouter J, Kowalski J, Foster J, Hass P, Zhang Z, Dillard-Telm L, et al. Identification of an angiogenic mitogen selective for endocrine gland endothelium. Nature 2001;412:877–84.[Medline]

14 Rafii S. Circulating endothelial precursors: mystery, reality, and promise. J Clin Invest 2000;105:17–9.[Free Full Text]

15 Jain RK. Barriers to drug delivery in solid tumors. Sci Am 1994;271:58–65.[Medline]

16 Helmlinger G, Netti PA, Lichtenbeld HC, Melder RJ, Jain RK. Solid stress inhibits the growth of multicellular tumor spheroids. Nat Biotechnol 1997;15:778–83.[Medline]

17 Padera TP, Yun C, Kadambi A, Mouta-Carreira C, Jain RK. Local mechanics and VEGF-C alter peri-tumor lymphatic function. Proc Am Assoc Cancer Res 2000;41:88.

18 Partanen TA, Alitalo K, Miettinen M. Lack of lymphatic vascular specificity of vascular endothelial growth factor receptor 3 in 185 vascular tumors. Cancer 1999;86:2406–12.[Medline]

19 Partanen TA, Arola J, Saaristo A, Jussila L, Ora A, Miettinen M, et al. VEGF-C and VEGF-D expression in neuroendocrine cells and their receptor, VEGFR-3 in fenestrated blood vessels in human tissues. FASEB J 2000;14:2087–96.[Abstract/Free Full Text]

20 Witmer AN, van Blijswijk BC, Dai J, Hofman P, Partanen TA, Vrensen GF, et al. VEGFR-3 in adult angiogenesis. J Pathol 2001;195:490–7.[Medline]

21 Breiteneder-Geleff S, Soleiman A, Kowalski H, Horvat R, Amann G, Kriehuber E, et al. Angiosarcomas express mixed endothelial phenotypes of blood and lymphatic capillaries: podoplanin as a specific marker for lymphatic endothelium. Am J Pathol 1999;154:385–94.[Abstract/Free Full Text]

22 Kriehuber E, Breiteneder-Geleff S, Groeger M, Soleiman A, Schoppmann SF, Stingl G, et al. Isolation and characterization of dermal lymphatic and blood endothelial cells reveal stable and functionally specialized cell lineages. J Exp Med 2001;194:797–808.[Abstract/Free Full Text]

23 Makinen T, Veikkola T, Mustjoki S, Karpanen T, Catimel B, Nice EC, et al. Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C/D receptor VEGFR-3. EMBO J 2001;20:4762–73.[Abstract/Free Full Text]

24 Johnston MG, Walker MA. Lymphatic endothelial and smooth-muscle cells in tissue culture. In Vitro 1984;20:566–72.[Medline]

25 Way D, Hendrix M, Witte M, Witte C, Nagle R, Davis J. Lymphatic endothelial cell line (CH3) from a recurrent retroperitoneal lymphangioma. In Vitro Cell Dev Biol 1987;23:647–52.[Medline]

26 Gumkowski F, Kaminska G, Kaminski M, Morrissey LW, Auerbach R. Heterogeneity of mouse vascular endothelium. In vitro studies of lymphatic, large blood vessel and microvascular endothelial cells. Blood Vessels 1987;24:11–23.[Medline]

27 Jackson DG, Prevo R, Clasper S, Banerji S. LYVE-1, the lymphatic system and tumor lymphangiogenesis. Trends Immunol 2001;6:317.

28 Banerji S, Ni J, Wang SX, Clasper S, Su J, Tammi R, et al. LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan. J Cell Biol 1999;144:789–801.[Abstract/Free Full Text]

29 Carreira CM, Nasser SM, di Tomaso E, Padera TP, Boucher Y, Tomarev SI, et al. LYVE-1 is not restricted to the lymph vessels: expression in normal liver blood sinusoids and downregulation in human liver cancer and cirrhosis. Cancer Res 2001;61:8079–84.[Abstract/Free Full Text]

30 Wigle JT, Oliver G. Prox1 function is required for the development of the murine lymphatic system. Cell 1999;98:769–78.[Medline]

31 Papoutsi M, Siemeister G, Weindel K, Tomarev SI, Kurz H, Schachtele C, et al. Active interaction of human A375 melanoma cells with the lymphatics in vivo. Histochem Cell Biol 2000;114:373–85.[Medline]

32 de Waal RM, van Altena MC, Erhard H, Weidle UH, Nooijen PT, Ruiter DJ. Lack of lymphangiogenesis in human primary cutaneous melanoma. Consequences for the mechanism of lymphatic dissemination. Am J Pathol 1997;150:1951–7.[Abstract]

33 Boucher Y, Brekken C, Netti PA, Baxter LT, Jain RK. Intratumoral infusion of fluid: estimation of hydraulic conductivity and implications for the delivery of therapeutic agents. Br J Cancer 1998;78:1442–48.[Medline]

34 Swartz MA, Berk DA, Jain RK. Transport in lymphatic capillaries: I. Macroscopic measurements using residence time distribution theory. Am J Physiol 1996;270:H324–9.[Abstract/Free Full Text]

35 Berk DA, Swartz MA, Leu AJ, Jain RK. Transport in lymphatic capillaries: II. Microscopic velocity measurement with fluorescence recovery after photobleaching. Am J Physiol 1996;270:H330–7.[Abstract/Free Full Text]

36 Jeltsch M, Kaipainen A, Joukov V, Meng X, Lakso M, Rauvala H, et al. Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. Science 1997;276:1423–5.[Abstract/Free Full Text]

37 Padera TP, Stoll BR, So PTC, Jain RK. High-speed intravital multiphoton laser scanning microscopy of microvasculature, lymphatics, and leukocyte-endothelial interactions. Mol Imaging 2002;1:9–15.[Medline]

38 Jain RK, Munn LL, Fukumura D. Molecular, anatomical and functional dissection of tumors using intravital microscopy. Nat Rev Cancer. In press 2002.

39 Eggert A, Ikegaki N, Kwiatkowski J, Zhao H, Brodeur GM, Himelstein BP. High-level expression of angiogenic factors is associated with advanced tumor stage in human neuroblastomas. Clin Can Res 2000;6:1900–8.[Abstract/Free Full Text]

40 Komura H, Kaneko S, Kaneko M, Nakanishi Y. Expression of angiogenic factors and tumor progression in human neuroblastoma. J Can Res Clin Oncol 2001;127:739–43.[Medline]

41 O-charoenrat P, Rhys-Evans P, Eccles SA. Expression of vascular endothelial growth factor family members in head and neck squamous cell carcinoma correlates with lymph node metastasis. Cancer 2001;92:556–8.[Medline]

42 Bunone G, Vigneri P, Mariani L, Buto S, Collini P, Pilotti S, et al. Expression of angiogenesis stimulators and inhibitors in human thyroid tumors and correlation with clinical pathological features. Am J Path 1999;155:1967–76.[Abstract/Free Full Text]

43 Niki T, Iba S, Tokunou M, Yamada T, Matsuno Y, Hirohashi S. Expression of vascular endothelial growth factors A, B, C, and D and their relationships to lymph node status in lung adenocarcinoma. Clin Can Res 2000;6:2431–9.[Abstract/Free Full Text]

44 Ohta Y, Nozawa H, Tanaka Y, Oda M, Watanabe Y. Increased vascular endothelial growth factor-C and decreased nm23 expression associated with microdissemination in lymph nodes in stage I non-small cell lung cancer. J Thorac Cardiovasc Surg 2000;119:804–13.[Abstract/Free Full Text]

45 Kajita T, Ohta Y, Kimura K, Tamura M, Tanaka Y, Tsunezuka Y, et al. The expression of vascular endothelial growth factor C and its receptors in non-small cell lung cancer. Br J Cancer 2001;85:255–60.[Medline]

46 Ohta Y, Shridhar V, Bright RK, Kalemkerian GP, Du W, Carbone M, et al. VEGF and VEGF type C play an important role in angiogenesis and lymphangiogenesis in human malignant mesothelioma tumours. Br J Cancer 1999;81:54–61.[Medline]

47 Akagi K, Ikeda Y, Miyazaki M, Abe T, Kinoshita J, Maehara Y, et al. Vascular endothelial growth factor-C (VEGF-C) expression in human colorectal cancer tissues. Br J Cancer 2000;83:887–91.[Medline]

48 George ML, Tutton MG, Janssen F, Arnaout A, Abulafi AM, Eccles SA, et al. VEGF-A, VEGF-C and VEGF-D in colorectal cancer progression. Neoplasia 2001;3:420–7.[Medline]

49 Kitadai Y, Amioka T, Haruma K, Tanaka S, Yoshihara M, Sumii K, et al. Clinicopathological significance of vascular endothelial growth factor (VEGF)-C in human esophageal squamous cell carcinomas. Intl J Cancer 2001;93:662–6.[Medline]

50 Yonemura Y, Endo Y, Fujita H, Fushida S, Ninomiya I, Bandou E, et al. Role of vascular endothelial growth factor C expression in the development of lymph node metastasis in gastric cancer. Clin Can Res 1999;5:1823–9.[Abstract/Free Full Text]

51 Ichikura T, Tomimatsu S, Ohkura E, Mochizuki H. Prognostic significance of the expression of vascular endothelial growth factor (VEGF) and VEGF-C in gastric carcinoma. J Surg Oncol 2001;78:132–7.[Medline]

52 Kabashima A, Maehara Y, Kakeji Y, Sugimachi K. Overexpression of vascular endothelial growth factor C is related to lymphogenous metastasis in early gastric carcinoma. Oncology 2001;60:146–50.[Medline]

53 Tang RF, Itakura J, Aikawa T, Matsuda K, Fujii H, Korc M, et al. Overexpression of lymphangiogenic growth factor VEGF-C in human pancreatic cancer. Pancreas 2001;22:285–92.[Medline]

54 Kurebayashi J, Otsuki T, Kunisue H, Mikami Y, Tanaka K, Yamamoto S, et al. Expression of vascular endothelial growth factor (VEGF) family members in breast cancer. Jpn J Cancer Res 1999;90:977–81.[Medline]

55 Gunningham SP, Currie MJ, Han C, Robinson BA, Scott PA, Harris AL, et al. The short form of the alternatively spliced flt-4 but not its ligand vascular endothelial growth factor C is related to lymph node metastasis in human breast cancers. Clin Cancer Res 2000;6:4278–86.[Abstract/Free Full Text]

56 Kinoshita J, Kitamura K, Kabashima A, Saeki H, Tanaka S, Sugimachi K. Clinical significance of vascular endothelial growth factor-C (VEGF-C) in breast cancer. Br Cancer Res Treat 2001;66:159–64.[Medline]

57 Hashimoto I, Kodama J, Seki N, Hongo A, Yoshinouchi M, Okuda H, et al. Vascular endothelial growth factor-C expression and its relationship to pelvic lymph node status in invasive cervical cancer. Br J Cancer 2001;85:93–7.[Medline]

58 Tsurusaki T, Kanda S, Sakai H, Kanetake H, Saito Y, Alitalo K, et al. Vascular endothelial growth factor-C expression in human prostatic carcinoma and its relationship to lymph node metastasis. Br J Cancer 1999;80:309–13.[Medline]

59 Jones A, Fujiyama C, Turner K, Fuggle S, Cranston D, Turley H, et al. Angiogenesis and lymphangiogenesis in stage I germ cell tumours of the testis. Br J Urology Int 2000;86:80–6.

60 Hirai M, Nakagawara A, Oosaki T, Hayashi Y, Hirono M, Yoshihara T. Expression of vascular endothelial growth factors (VEGF-A/VEGF-1 and VEGF-C/VEGF-2) in postmenopausal uterine endometrial carcinoma. Gynecol Oncol 2001;80:181–8.[Medline]


This article has been cited by other articles in HighWire Press-hosted journals:


             
Copyright © 2002 Oxford University Press (unless otherwise stated)
Oxford University Press Privacy Policy and Legal Statement