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Steele Laboratory for Tumor Biology, Departments of Radiation Oncology [C. M. C., E. d. T., T. P. P., Y. B., R. K. J.] and Pathology [S. M. N.], Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, and Laboratory of Molecular and Developmental Biology, National Eye Institute, NIH, Bethesda, Maryland 20892 [S. I. T.], Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, Maine 04074 [C. M. C.]
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ABSTRACT |
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Introduction |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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The only known ligand for LYVE-1 is HA, a ubiquitous extracellular matrix molecule with proinflammatory, angiogenic, and cell migratory functions (6)
. The continuous turnover of HA involves clearance by tissue lymphatics, followed by degradation in the lymph nodes and LSECs. LYVE-1 functions in lymphatics, whereas the HARE functions in LSECs (7)
. But, in fact, the biochemical mechanisms of HA degradation remain largely unknown, e.g., it is still not known how cirrhosis and HCC lead to impaired HA degradation by LSECs, with concomitant increases in serum HA levels. A related question is which HA receptor is impaired in cirrhosis and HCC (8)
. HCC usually evolves from cirrhosis and is one of the most common malignancies worldwide, with a growing incidence of 
1,000,000 new cases/year (9)
. A better understanding of the HA receptors within the liver microcirculation may provide critical information into the treatment of these diseases. On the basis of these observations, we hypothesize that LYVE-1 is also present in normal liver blood sinusoids. We studied LYVE-1 expression in the lymphatic and the blood microcirculation of both normal and diseased livers and provide the first supporting evidence for regulation of LYVE-1 in human liver cancer and cirrhosis. In addition, we present the first study on the distribution of lymphatics in HCC and liver metastases.
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Materials and Methods |
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Animals.
Athymic NCr/Sed Nude, RAG2, CB-17/ICR-SCID/Sed, C3H/Sed, and FVB/NJ female mice, 8–9 weeks of age, were bred and maintained in our defined flora- and specific pathogen-free animal colony. C57BL/6J were obtained from The Jackson Laboratory (Bar Harbor, ME). All procedures were carried out following Institutional Animal Care and Use Committee approval.
IHC Analysis.
IHC for LYVE-1 was done according to published methods (5)
using the antimouse and antihuman LYVE-1 antisera, kindly provided by Dr. David Jackson (Oxford University, Oxford, United Kingdom). Mouse antihuman endothelial cell CD31 monoclonal antibody (clone JC/70A) was from Dako Corp. (Carpinteria, CA). IHC for Prox 1 was adapted to paraffin sections, from previous studies with frozen tissues (10
, 11)
, as follows. Briefly, mouse tissues were fixed by vascular perfusion of 4% paraformaldehyde in PBS as published (12)
, dehydrated, and embedded in paraffin. Sections (5 µm thick) were dried for 4–10 h at 37°C, dewaxed in xylene, and rehydrated in graded ethanol. After comparing six antigen retrieval methods, which produced equivalent results, we chose the following conditions: microwave retrieval [4 min on full power (950 W), followed by 6 min on 10% power] in low pH target retrieval solution (Dako Corp.), followed by 20 min at room temperature. Sections were rinsed in PBS [0.01 M phosphate buffer, 0.138 M NaCl, and 0.0027 M KCl (pH 7.4)] and soaked for 30 min at room temperature in methanol containing 3% hydrogen peroxide (Sigma Chemical Co., St. Louis, MO). Nonspecific binding of antibodies to sections was blocked for 30 min at room temperature in PBS containing 10% goat serum (Jackson Immunoresearch Laboratories, Inc., West Grove, PA), 5% BSA (Jackson Immunoresearch Laboratories), and 0.3% Triton X-100. We used three different Prox 1 antibodies, which were characterized previously (10
, 11)
: (a) rabbit antiserum (1:1,000–1:10,000 dilution) obtained against a glutathione S-transferase-fusion protein containing homeo- and prospero domains of human Prox 1; (b) purified IgG fraction of this antiserum (1:500–1:6,000 dilution); and (c) purified IgG fraction (1:500–1:4,000) of antiserum raised only against the prospero domain of human Prox 1. The best signal-to-noise ratio was typically seen with the third one. Sections were incubated for 30 min to 1 h with primary antibodies diluted in blocking buffer. Negative controls were done by substituting the immune sera with nonimmune rabbit serum or negative control rabbit IgG (Dako Corp.) or by omitting the primary antibodies. No positive staining was obtained in these cases. Liver tissue-bound primary antibodies were detected using the Envision Peroxidase/Diaminobenzidine Systems (Dako Corp.). The Avidin Biotin Complex Vectastain Elite Peroxidase-based systems (Vector Laboratories, Inc., Burlingame, CA) with diaminobenzidine as the substrate (Sigma Chemical Co.) was used for all other tissues. Positive stainings were brown nuclei (Prox 1) and brown cell membranes (for LYVE-1 and CD31). Sections were counterstained with hematoxylin and mounted in Permount (Sigma Chemical Co.).
Lectin Perfusion.
Biotinylated Lycopersicon esculentum lectin (Vector Laboratories) was injected systemically at 10 µg/gram of body weight 5 min before perfusion fixation. The livers were then processed as above. Vessel wall-bound lectin was detected with the Avidin Biotin Complex Vectastain Elite Peroxidase-based system.
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Results |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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. Our results show that, in all six strains, normal liver blood sinusoids also express LYVE-1 (Fig. 1, a and b)
; in addition, they stain for L. esculentum agglutinin, confirming blood perfusion of these LYVE-1-expressing vessels (Fig. 1c)
. The most intense sinusoidal LYVE-1 signal is seen in the metabolic Zone 2 of the murine liver acini (Fig. 1b)
. In contrast, LYVE-1 expression is absent from the arterial and venular endothelium (Fig. 1, a and b)
. The same pattern is seen in normal human liver (Fig. 1d)
. Finally, we found that the LYVE-1 antigen is present in both the LSECs and Kupffer cells. Kupffer cells, which are resident liver macrophages located within the liver sinusoidal lumen, were identified as LYVE-1- and CD68-double-positive cells in adjacent liver sections (data not shown). Importantly, in both mouse and human, blood sinusoids of the spleen and bone marrow do not express LYVE-1 ( Ref. 5
and data not shown).
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for data in the mouse colon). More pertinent to this study is the evidence that, in the liver, Prox 1-LYVE-1-double-positive vessels are only identifiable in the portal tracts and capsule (Fig. 1f
and data not shown) and not in the parenchyma. This is the expected distribution for normal liver lymphatics (15)
. Thus, Prox 1 staining (but not LYVE-1) is a means to identify a specific vessel as being a lymphatic in the liver. However, note that not all Prox-positive cells are endothelial cells; our data (Fig. 1f
and data not shown), as well as those of others, show that hepatocytes and some photoreceptors also express Prox 1. In fact, hepatocytes and photoreceptors are dependent on this transcription factor for proper differentiation (13)
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Angiogenic and Remodeling Blood Vessels of HCCs and Cirrhotic Nodules Show Lower LYVE-1 Expression than the Normal Sinusoidal Counterparts.
Repeated liver injury by chronic hepatitis or drug or alcohol abuse can cause cirrhosis, the fibrous scarring of the liver (15)
. Elevated serum HA associated with cirrhosis is either caused by impaired degradation by the liver endothelium, increased output by activated Ito cells, or both (8)
. Thus, we hypothesized that decreased levels of the scavenging HA receptor LYVE-1 are associated with cirrhosis. Immunoperoxidase staining of adjacent sections for the endothelial marker CD31 (16)
and for LYVE-1 revealed that, contrary to normal human hepatic sinusoids (Fig. 1d)
, LYVE-1 is only sparsely expressed in the parenchymal sinusoid-like vessels of cirrhotic livers (Fig. 2a)
. The LYVE-1-positive vessels within the fibrous tissue also express Prox 1 and, thus, are more likely to be lymphatics. Moreover, LYVE-1 is also typically absent from human HCC regardless of whether there is underlying cirrhosis in the surrounding liver (Fig. 2c
; compare top and bottom panels) or not (Fig. 2b
; again, compare top and bottom panels). In liver metastases, the tumor vasculature is CD31 positive (Fig. 2d
, top panel); however, LYVE-1 staining is not associated with the blood vessels either (Fig. 2d
, bottom panel). Thus, CD31 is elevated and LYVE-1 expression in LSECs is decreased in both liver dysplasias, when compared with the normal liver.
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shows a representative case of the results we obtained. Both in HCC (16 of 16) and in liver metastases (9 of 9), we found that lymphatics were not present within the tumor parenchyma or in the intratumor septa of connective tissue. However, they were visible in the fibrous areas that separate the tumors from the remaining liver (tumor capsule) and more abundant in the regions further away from the tumor nodules. In the cases where there was no clearly defined capsule, lymphatics were also restricted to the outer tumor margins. In other words, lymphatics were not seen within the core of liver tumors but were abundant in their immediate vicinity. These results were corroborated additionally by the absence of LYVE-1-positive vessels from a total of 25 HCCs and 17 metastatic adenocarcinomas (data not shown). We cannot exclude the possibility that there are lymphatics that do not stain for either Prox 1 or LYVE-1. Finally, because Prox 1-stained vessels typically stained with LYVE-1, these results also suggest that LYVE-1 is not down-regulated in the lymphatics in cirrhosis and HCC.
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Discussion |
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As an HA scavenging receptor, LYVE-1 could conceivably have a role in liver-specific functions. Considerations of kinetics and ligand-specificity make it unlikely that LYVE-1 is the main receptor for uptake of HA by LSEC (5) and more likely to function either in concert with HARE or in another HA-related process. Importantly, the HARE complex has not been sequenced or fully characterized yet, but HARE and LYVE-1 show very different tissue distribution patterns and kinetic properties, and antibodies to either molecule do not cross-react.5 LYVE-1 homology to CD44 is also a suggestive link to the immunoregulatory functions of LSECs (24) .
Implications of the Differential LYVE-1 Expression in Cirrhosis and HCC.
Whereas the reduction in LYVE-1 expression was evident in the blood vessels of HCC and cirrhosis, we did not observe a reduction in LYVE-1 in the lymphatics, suggesting cell-specific responses to the HCC and cirrhotic liver microenvironment. Interestingly, the most prominent difference in the liver vasculature in HCC and cirrhosis is that sinusoids appear more like capillaries–so called sinusoidal "capillarization." The hallmarks of this process of endothelial dedifferentiation are the decrease in both the diameter and the number of fenestrae, the formation of basement membranes underlying the LSECs (19)
, and the associated increase in the levels of serum HA. Transforming growth factor ß has a major role in cirrhosis, inducing a decrease in the surface density of LSEC fenestrae and an increase in the synthesis of HA by Ito cells (reviewed in Ref. 25
). Our results do not allow us to determine which aspect of sinusoidal "capillarization" leads to, or is influenced by, the altered LYVE-1 expression. Nevertheless, they do provide the first association between cirrhosis, HCC, and reduced levels of a cell-surface receptor for HA metabolism in vivo. In contrast to LYVE-1, CD44 is not normally expressed in LSECs but is up-regulated in rat cirrhotic liver (23)
and in patients prone to cirrhosis because of alcoholic liver disease (26)
. Future studies are needed to evaluate how LYVE-1 expression correlates with the stage of liver disease in patients. Cirrhosis and tumor-induced alterations in LYVE-1 expression in the liver microcirculation could have important implications for the diagnosis and treatment of liver disease. Finally, it should be studied whether reagents that target LYVE-1 are a means for radioimmunodetection of cirrhosis and HCC.
Differential Lymphangiogenesis between Cirrhosis and Human Liver Tumors.
Our present report is also the first study using two recently identified lymphatic markers, LYVE-1 and Prox 1, to characterize the distribution of lymph vessels in human liver tumors. Interestingly, because lymphatics are restricted to the portal tracts and the Glisson’s capsule of normal livers, their presence within the parenchymal fibrous areas that develop de novo in cirrhosis suggests that cirrhosis is accompanied by lymphangiogenesis. This is consistent with previous suggestions that increased lymph production in viral liver disease leads to lymphatic proliferation (27)
. On the other hand, we found only peritumoral lymphatics in liver cancer; lymphatics were not observed in the tumor parenchyma or between tumor nodules. These results are consistent with our previous lymphangiographic study in murine tumors (2)
. Intratumoral lymphatics have been identified in certain animal models (reviewed in Refs. 1
and 3
), but, to date, no similar study has been done for liver tumors.
There is a remarkable contrast between the conspicuous presence of blood vessels throughout the liver (normal, cirrhotic, and cancer) and the concentration of the lymphatics in connective tissue. Lymphangiogenesis and lymph vessel survival may respond to mechanical and biochemical cues abundant within connective tissue; these cues may be absent from the intratumor microenvironment or overridden by lymphangiostatic factors (none of which has been identified to date), including the mechanical stress generated by cancer cells (28) . These are open questions, because the physiological and pathological stimuli driving lymph vessel proliferation are not known. We do know that angiogenesis is partly driven by oxygen and nutrient diffusion limits that establish a survival-based need for blood vessels at specific distances from normal cells. But is there any similar need for lymphatics? Is there any counterpart to hypoxia-driven angiogenesis in lymphangiogenesis? In other words, what are the sensors that trigger lymphangiogenic responses: pressure, pH, redox, or other possible indicators of a need for a drainage system? Future studies should address these questions, as well as determine whether the absence of lymphatics within HCCs and liver metastases is an impediment for molecular and cellular transport in human liver tumors.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported in part by NIH Grant R24 CA85140 (to R. K. J.) and by National Science Foundation and Whitaker Fellowships (to T. P. P.). 
2 Present address: Center for Molecular Medicine, Maine Medical Center Research Institute, 81 Research Drive, Scarborough, ME 04074.
3 To whom requests for reprints should be addressed, at Steele Lab, Department of Radiation Oncology, Massachusetts General Hospital, 100 Blossom Street, Boston, MA 02114. Phone: (617) 726-4083; Fax: (617) 724-1819; E-mail: jain{at}steele.mgh.harvard.edu
4 The abbreviations used are: LYVE, lymphatic vessel endothelial hyaluronan receptor; HA, hyaluronan; HARE, hyaluronan receptor for endocytosis; HCC, hepatocellular carcinoma; IHC, immunohistochemistry; LSECs, liver sinusoidal endothelial cells.
5 P. Weigel, personal communication.
Received 8/ 7/01. Accepted 10/ 3/01.
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REFERENCES |
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 T. P. Padera, A. Kadambi, E. di Tomaso, C. M. Carreira, E. B. Brown, Y. Boucher, N. C. Choi, D. Mathisen, J. Wain, E. J. Mark, et al. Lymphatic Metastasis in the Absence of Functional Intratumor Lymphatics Science, June 7, 2002; 296(5574): 1883 - 1886. [Abstract] [Full Text] [PDF]
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 G. Oliver and M. Detmar The rediscovery of the lymphatic system: old and new insights into the development and biological function of the lymphatic vasculature Genes & Dev., April 1, 2002; 16(7): 773 - 783. [Full Text] [PDF]
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A. J. Grant, S. Goddard, J. Ahmed-Choudhury, G. Reynolds, D. G. Jackson, M. Briskin, L. Wu, S. G. Hubscher, and D. H. Adams Hepatic Expression of Secondary Lymphoid Chemokine (CCL21) Promotes the Development of Portal-Associated Lymphoid Tissue in Chronic Inflammatory Liver Disease Am. J. Pathol., April 1, 2002; 160(4): 1445 - 1455. [Abstract] [Full Text] [PDF]
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 R. K. Jain and B. T. Fenton Intratumoral Lymphatic Vessels: A Case of Mistaken Identity or Malfunction? J Natl Cancer Inst, March 20, 2002; 94(6): 417 - 421. [Full Text] [PDF]
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 R.K. JAIN Angiogenesis and Lymphangiogenesis in Tumors: Insights from Intravital Microscopy Cold Spring Harb Symp Quant Biol, January 1, 2002; 67(0): 239 - 248. [Abstract] [PDF]
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