Review article
Tumor Lymphangiogenesis and Lymphangiogenic Growth Factors

https://doi.org/10.1016/j.arcmed.2007.12.005Get rights and content

Recent studies have revealed that malignant tumors can actively induce the formation of new lymphatic vessels and metastasize through the lymphatic system. Tumor-induced lymphangiogenesis driven by tumors expressed lymphangiogenic growth factors such as VEGF family, fibroblast growth factor 2 (FGF-2), angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), and platelet-derived growth factors (PDGFs) is correlated with lymph node metastasis in experimental cancer models and in several types of human cancers. Tumor- induced lymphangiogenesis has now been firmly established as a novel mechanism for cancer progression and lymph node metastasis. Recent studies indicate that blockade of the lymphangiogenic growth factors pathway inhibits tumor spread to lymph nodes and likely beyond. The potential effects of most of these newly identified lymphatic growth factors on tumor-induced lymphangiogenesis and lymph node metastasis remain to be further investigated. A number of questions remain to be answered concerning the potential efficacy of targeting at tumor-induced lymphangiogenesis for inhibiting tumor spread to lymph nodes.

Introduction

Lymphatic metastasis is frequent and has a major negative prognostic effect in many tumor sites, usually justifying administration of postoperative systemic therapy to decrease the risk of metastatic relapse (1). However, the mechanisms of lymph node metastasis were studied only very recently. A major impediment to gaining such knowledge has been the lack of markers with which to isolate and study lymphatic endothelium (2). This has now been overcome with the discovery of molecules such as the lymphatic endothelial hyaluronan (HA) receptor LYVE-1, which represents a new and valuable tool for such research (3). 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 (4). Many studies over the past few years have substantiated that lymphangiogenesis, driven by tumors expressing lymphangiogenic growth factors such as VEGF-C or VEGF-D, is able to promote metastasis to regional lymph nodes. The increased density of lymphatic vessels increases the probability that invasive tumor cells are able to enter the lymphatics and thereby be transported to regional lymph nodes. Progress in the molecular mechanisms of lymphangiogenesis during tumor growth raises hopes for the development of new targeted therapies designed to prevent the appearance of lymph node and/or visceral metastasis (5). Given that most primary tumors are removed surgically, an antimetastatic therapeutic strategy could be useful for restricting the spread of tumor cells from remnants of primary tumors not removed during surgery, from inoperable primary tumors or from preexisting cancer metastases. This review will summarize the expanding list of lymphangiogenic growth factors that may be relevant to tumor lymphangiogenesis. These molecules may be important potential targets for therapeutic approaches designed to restrict lymph node metastasis by blocking tumor lymphangiogenesis.

It was long supposed that lymphatic metastasis was a passive process involving detached tumor cells reached lymph nodes via preexisting afferent lymphatic channels following natural routes of lymph drainage, especially wide open intercellular junction of lymphatic endothelial cells (LECs) (6). However, in the past few years, it has become clear that one mechanism that promotes metastasis to regional lymph nodes is tumor-induced lymphangiogenesis, the formation of new lymphatics, which ultimately controlled by a complex network of growth factors, cytokines and chemokines can contribute actively to tumor metastasis 5, 7, 8. The prevailingly established view that lymphangiogenesis does not occur within the tumor tissues is being challenged by recent studies 9, 10. Several experiments in genetic and xenotransplant tumor models have suggested that expression of lymphangiogenic growth factors led to formation of new tumor-associated lymphatics either within or at the periphery of the tumors 8, 11, 12. This was accompanied by enhanced lymphatic metastasis and, in some cases, by distant organ metastasis 8, 11, 12. Analysis of lymphatic vessels in cancer was problematic in the past because of the lack of specific lymphatic endothelium markers—it was therefore difficult to discriminate between blood vessels and lymphatics. This situation has improved in recent years with the advent of lymphatic markers such as LYVE-1, Prox-1, and podoplanin 3, 13. Such markers have facilitated clinicopathological analyses of lymphangiogenesis in human cancer. Recent evidence indicates that tumor cells can also induce lymph node lymphangiogenesis before they metastasize, and that metastastic tumor cells continue to induce lymphatic vessel growth within sentinel lymph nodes, possibly promoting their further metastatic dissemination 14, 15, 16. An increasing number of clinicopathological investigations have shown a direct relationship between the expression of VEGF-C/-D and metastasis in human tumors 17, 18. Efforts have recently been made to elucidate interactions between tumor tissues and intratumoral lymphatics (ITLs) or peritumoral lymphatics (PTLs), which are evidently necessary for the invasion, intravasation, and extravasation of malignant cells. However, some important issues are still controversial. Many authors consider that lymph node metastasis can only occur via peritumoral lymphatics because intratumoral lymphatics may not be functional due to the high interstitial pressure within the tumor 2, 9. However, some studies have demonstrated a relationship between the presence of intratumoral lymphatics, lymph node invasion and poor prognosis in patients operated on for squamous cell carcinoma of the head and neck (19), melanoma (10), and papillary thyroid carcinoma (20). Similarly, although the majority of studies reported the non-functional nature of intratumoral lymphatics, other studies have demonstrated the presence of cycling lymphatic endothelial cells and tumor emboli in these vessels (21). These discordant appearances probably depend on the tumor model studied. Nevertheless, metastatic spread to lymph nodes in some models occurred in the absence of tumor lymphangiogenesis, perhaps via the PTLs that preexist before tumor development, indicating that the PTLs may be sufficient for disseminating tumor cells to local and more distal lymph nodes (22). It will be important in the future to define which tumors are dependent on lymphangiogenesis for metastatic spread and which lymphangiogenic growth factors are required for these processes.

The best-studied lymphangiogenic signaling system in cancer is the VEGF-C/VEGF-D/VEGFR-3 signaling axis. VEGFR-3 is a cell surface receptor tyrosine kinase predominantly expressed on the surface of lymphatic endothelial cells in adults (23). Its ligands are VEGF-C and VEGF-D, members of the VEGF family 24, 25. VEGF-C and VEGF-D are secreted in the form of weakly biologically active proteins. Successive proteolyses of N- and C-terminal domains increase the affinity of ligands for VEGFR-3. This proteolysis is catalyzed by plasmin (for VEGF-D and VEGF-C) and enzymes of the proprotein convertase family, PC5, PC7 and furine (for VEGF-C) (26). Activation of VEGFR-3 by its ligands induces heterodimerization of the receptor, activation of its intracellular tyrosine kinase domain, and intracellular signal transduction leading to proliferation of lymphatic endothelial cells, growth of lymphatic vessels and, potentially, to effects on the expression of molecules by lymphatic endothelial cells. The lymphangiogenic activity of VEGF-C/VEGF-D/VEGFR-3 axis has been demonstrated in several in vivo and in vitro models involving transgenesis, gene ablation or adenoviral gene delivery (26). Overexpression of VEGF-C and/or VEGF-D by tumor cells in xenograft or transgenic cancer models increased the peritumoral and/or intratumoral lymphangiogenesis, promoted metastasis to local lymph nodes and, in some studies, facilitated distant organ metastasis 5, 8, 9. The VEGF-C/VEGFR-3 axis enhances cancer cell mobility and invasiveness and contributes to the promotion of cancer cell metastasis in various types of cancer including lung adenocarcinoma, breast cancer, cervical cancer, prostate cancer, and colorectal cancer (27). Importantly, inhibition of this signaling pathway decreased the abundance of lymphatic vessels in tumor and the incidence of lymph node metastasis in some tumor models 11, 12, 28, 29. These studies suggest there may be potential benefit in blocking this signaling system in human cancer in order to restrict metastasis. The role of the VEGF-C/VEGF-D/VEGFR-3 axis has also been evaluated in human tumors over recent years. The majority of investigations demonstrate a positive correlation between VEGF-C/-D expression by tumor cells and lymphatic invasion, lymph node involvement and distant metastasis and, in some instances, poor clinical outcomes, although several contradictory results have been reported 5, 21. VEGF-C/-D can facilitate metastasis by increasing the surface area of tumor cells in contact with LECs by increasing vascular permeability and/or by changing LEC adhesive properties or cytokine/chemokine expression (30). Other studies have also shown that tumor cells may express VEGFR-3 and that VEGFR-3 is also a factor for poor prognosis 31, 32. Two studies showed a negative impact of VEGF-C expression by tumor cells on survival, but without any correlation with lymph node invasion 31, 33. Some of these discordant results could be explained by the fact that almost all studies conducted in human tumors only evaluated the expression of VEGF-C or VEGF-D in tumor cells, but it has been demonstrated that these factors are also secreted by macrophages, perivascular stromal cells, and platelets (34). Further studies are therefore necessary to more precisely define the role of the VEGF-C/VEGF-D/VEGFR-3 axis in human tumors.

In addition to members of the VEGF family, other growth factors such as FGF-2, Ang-1, Ang-2, and PDGFs have also been shown to induce lymphangiogenesis in vivo.

Cyclooxygenase (COX) is the key enzyme in the conversion of arachidonate to a series of prostaglandins (PGs) and thromboxanes. Two prominent isoforms of this enzyme, i.e., COX-1 and COX-2, have been identified. COX-1 is known as a housekeeping gene and is constitutively expressed in most tissues, plays a role in regulating normal physiological function and inflammation (35). COX-2 is an inducible gene product whose expression is enhanced by various stimuli such as inflammation, cytokines, tumor promoters, and growth factors 36, 37. Constitutional COX-2 expression has been described in many tumor sites and is associated with tumor aggressiveness and poor prognosis (37). There have been data indicating that COX-2 plays a role in tumor angiogenesis, resistance to apoptosis, tumor invasion and metastatic processes, and anti-tumor immunity (38). Recently, COX-2 was shown to be an upregulator of VEGF-C in lung adenocarcinoma (39) and breast cancer (40), suggesting a role as a promoter of lymphangiogenesis. Several studies conducted in human tumors have shown a correlation between VEGF-C and COX-2 expression by tumor cells, and a correlation between their expression, lymphatic microvascular density, and lymphatic invasion 39, 40, 41. Cyclooxygenase-2 inhibitors are showing great promise for their potential therapeutic benefit in anti-lymphangiogenesis activity in vitro(42). Cyclooxygenase-2 inhibition decreases tumor growth in a xenograft model of breast cancer and may potentially decrease recurrence by inactivating AKT and decreasing new lymphatic vessel formation (43).

FGF-2 is a heparin-binding protein that induces proliferation and differentiation of a variety of cell types (44). FGF-2 is able to induce both angiogenesis and lymphangiogenesis and upregulates VEGF-C and VEGF-D expression in the mouse cornea model 45, 46. Use of neutralizing VEGFR-3 antibodies blocks the FGF-2-induced lymphangiogenesis, indicating that FGF-2 promotes lymphatics growth via the VEGF-C/VEGF-D/VEGFR-3 signaling axis 45, 47. The role of FGF-2 in promoting tumor lymphangiogenesis therefore needs to be confirmed in animal models and human cancers. Recent evidence suggests that lymphangiogenic activity of FGF-2 in lymphatic endothelial cells is mainly through the Akt/mammalian target of rapamycin (mTOR)/p70S6 kinase pathway and active molecular interactions between the tumor and lymphatic endothelium via FGF-2 (48). These data suggest that the pathway provides a potent target for tumor lymphangiogenesis. Further histochemical analysis using an in vivo lymphangiogenic model is required to support these findings.

Angiopoietins are ligands of the endothelial cell surface receptor tyrosine kinase Tie2 and are expressed on the surface of endothelial cells. Ang-1 activates Tie2 and functions as a positive regulator of remodeling and stabilization of blood vessels, whereas Ang-2 inhibits Tie2 and acts as a negative regulator of angiogenesis. Ang-1 is essential for embryonic vascular development, whereas Ang-2 is dispensible for this process but is required for postnatal vascular remodeling (49). Recently, Ang1 and Ang2 have been reported to regulate the formation of lymphatic vessels through their receptor Tie2 50, 51. During development, loss of Ang-2 results in major defects in patterning and function of the lymphatic vascular network that can be rescued by Ang-1, indicating that Ang-2 is crucial for lymphatic vessel development (50). It has been reported that Ang-1 promotes lymphangiogenesis in the mouse cornea model (51) and lymphatic vessel hyperplasia when expressed in the skin of transgenic mice or when delivered to mouse skin using viral expression vectors (52). Ang-1-induced sprouting of lymphatic vessels is blocked by a soluble form of VEGFR-3, suggesting that the VEGF-C/VEGF-D/VEGFR-3 axis is involved in Ang-1-mediated lymphangiogenic signaling (52). The lymphangiogenic action of Ang-1 appears to be exerted indirectly via increased expression of VEGFR-3 on the surface of lymphatic endothelial cells.

PDGFs are secreted dimeric glycoprotein ligands whose biological activities are mediated by three forms of tyrosine kinase receptors encoded by two gene products, PDGFR-α and PDGFR-β (53). There are five different disulfide-linked dimers including three old members of dimeric forms of two gene products; PDGF-AA, PDGF-AB and PDGF-BB, and two new members of homdimers; PDGF-CC and PDGF-DD (54). Members of the PDGF family are often expressed at high levels in many malignant tissues (53). PDGF receptor signaling plays a role in multiple facets of tumor biology including autocrine stimulation of tumor cell proliferation, promotion of tumor angiogenesis and recruitment of stromal fibroblasts (53). A recent study in a mouse fibrosarcoma model showed that expression of PDGF-BB induced tumor lymphangiogenesis, causing formation of intratumoral lymphatics that led to enhanced metastasis to lymph nodes (55). This study suggests that PDGF-BB may act as potently as VEGF-C in vivo in inducing intratumoral lymphangiogenesis without mediation via the VEGF-C/-D/VEGFR-3 pathway (55). Thus, development of PDGF antagonists such as Gleevec may become an important therapeutic approach for cancer therapy.

The IGF signaling system consists of two secreted ligands (IGF-1 and IGF-2), two cell surface receptors (IGF-1R and IGF-2R), and several IGF-binding proteins (IGFBPs) 56, 57. Both IGF-1 and IGF-2 induce angiogenesis in several in vitro and in vivo systems 58, 59. IGFBPs may modulate the biological activity of IGFs (60). In addition to cell growth-promoting activity, IGFs are also potent survival factors that may prevent cellular apoptosis of tumor cells, blood vessel endothelial cells, and lymphatic endothelial cells 61, 62, 63. A recent study reported that IGF-1 and IGF-2 promoted proliferation and chemotaxis of cultured primary lymphatic endothelial cells that express IGF-1R and IGF-2R on the surface (56). Both IGF-1 and IGF-2 were also shown to promote growth of lymphatic vessels in the mouse cornea model, and the IGF-1-induced lymphangiogenesis could not be inhibited by the soluble fragment of VEGFR-3, indicating that IGF-1-mediated lymphangiogenic signaling is independent of the VEGF-C/VEGF-D/VEGFR-3 axis (56). The finding that IGF-1 and IGF-2 promote lymphangiogenesis indicates multiple roles of IGFs in promoting tumor growth. Inversely, in a Lewis lung carcinoma model, IGF-1R promoted expression of VEGF-C and lymph node metastasis, suggesting that this receptor could act as a positive regulator of VEGF-C in cancer and therefore promote lymphatic metastasis (64). Although these data indicate that IGFs could conceivably play a role in tumor lymphangiogenesis, other studies are necessary to specify the role of IGF in tumor lymphatics and lymph node metastasis. Thus, development of IGF antagonists may be an important approach for the treatment of cancer and metastasis.

HGF is a glycoprotein synthesized by various cells of mesenchymal origin 65, 66. HGF, also known as scatter factor, is a mediator of liver regeneration, stimulates migration and proliferation of several cell types especially endothelial cells, and participates in tissue repair and tumor invasiveness. Its activities are mediated by binding to a cell surface receptor tyrosine kinase known as HGF-R or MET/c-met. Several studies have indicated a correlation between c-met expression or the occurrence of c-met-activating mutations and the metastatic spread of cancer (67). A recent study reported that c-met is expressed on cultured lymphatic endothelial cells and by regenerating lymphatic endothelium during tissue repair. In vitro HGF promotes proliferation, migration and formation of tube by cultured lymphatic endothelial cells independent of the VEGF-C/VEGF-D/VEGFR-3 axis signaling. In vivo HGF stimulates lymphangiogenesis in transgenic mice models, indicating that it can act as a lymphangiogenic growth factor and is a candidate molecule for promoting tumor lymphangiogenesis (65). Another study reported that the hepatocyte growth factor secreted by tumor cells has shown an ability to stimulate PTLs growth via VEGFR-3-mediated signaling pathway (68). Further confirmation studies are expected.

VEGF-A was previously thought to act as a secreted specific blood angiogenic factor through activation of cell surface receptor tyrosine kinases VEGFR-1 and VEGFR-2, which were expressed on the endothelium of blood vessels (69). VEGFR-2 can also be expressed on endothelial cells of some lymphatic vessels (70). However, some recent studies have shown the role of VEGF-A in inducing lymphangiogenesis in several animal models 15, 71, 72. In a chemically induced skin carcinogenesis model, VEGF-A has not only strongly promoted multistep skin carcinogenesis, but also induced active proliferation of tumor-associated lymphatics and sentinel lymph node lymphangiogenesis even before metastasizing (15). Likewise, in a mouse tumor xenograft model, VEGF-A expression by fibrosarcoma cells promoted the growth of peritumoral lymphatics and lymph node metastasis (73). Several clinical studies have reported a correlation between VEGF-A expression by tumor cells and the incidence of lymph node metastasis in colorectal cancers, esophageal cancers, and squamous cell carcinomas of the head and neck 74, 75, 76. The newly identified phenomenon of “lymph node lymphangiogenesis” may further facilitate metastatic tumor spread throughout the lymphatic system. However, contradictory results have been obtained in various animal models of tumor lymphangiogenesis. VEGF-A did not promote lymphangiogenesis or lymph node metastasis in 293EBNA cell xenograft model, whereas expression of VEGF-D promoted both of these effects (11). VEGF-A did not promote lymph node metastasis in a transgenic pancreatic tumor model (77). These apparently contradictory results can probably be explained by differences in the levels of expression of VEGFR-2 on the endothelium of lymphatic vessels in the vicinity of a tumor, by the type of VEGF-A isoforms secreted, and by the type of stromal cells recruited in response to VEGF-A and that express VEGF-C/D (26). The molecular mechanism by which VEGF-A promotes tumor lymphangiogenesis and metastasis is not yet clear and may therefore be either direct or indirect (78): direct via activation of VEGFR-2 on the surface of lymphatic endothelial cells or indirect via increased secretion of VEGF-C and VEGF-D by intratumoral macrophages. Should an indirect mechanism be the case, targeting the VEGF-C/VEGF-D/VEGFR-3 system might be sufficient to block VEGF-A-induced tumor lymphangiogenesis. In the case of a direct mechanism, Avastin (Genentech, South San Francisco, CA) could be used to block the contribution of VEGF-A to lymphangiogenic signaling via VEGFR-2 in human cancer. However, Avastin would not restrict lymphangiogenesis or lymphatic metastasis promoted by VEGF-C or VEGF-D because this antibody does not bind these growth factors. Instead, a combination of reagents targeting the VEGF-A/VEGFR-2 and VEGF-C/VEGF-D/VEGFR-3 signaling pathways would be required (26).

NO is produced by three isoforms of nitric oxide synthases (NOS): the calcium-dependent endothelial NOS (eNOS), inducible NOS (iNOS), and neuronal NOS (nNOS) (79). NO regulates a number of signaling processes; in the vascular system, NO effects include vasodilation and increased vascular permeability (80). Soluble guanylate cyclase (sGC) is the only known physiological receptor for NO. sGCs play a major role in the mediation of normal and pathological blood vascular angiogenesis (81), and inhibition of sGC suppresses neovascularization in the chicken chorioallantoic membrane assay (82). Recent studies have shown that NO is produced and released by lymphatic endothelial cells, possibly regulating lymphatic permeability and flow and that stimulation of iNOS activity in tumors is correlated with expression of the lymphangiogenic growth factor VEGF-C and VEGF-D 83, 84, 85. Kajiya et al. found that LECs specifically express the α1β1 isoform of sGC, that vascular endothelial growth factor-A potently induces sGCα1β1, and that NO induced LEC proliferation, migration, and cGMP production in LECs are specifically dependent on sGCα1β1. Moreover, the specific sGC inhibitor NS-2028 completely prevents ultraviolet B-irradiation-induced lymphatic vessel enlargement, edema formation, and skin inflammation in vivo. These findings identify a crucial role of the NO/sGCα1β1/cGMP pathway in modulating lymphatic vessel function. The blockade of sGCα1β1 signaling might serve as a novel therapeutic strategy for inhibiting lymphangiogenesis and inflammation, in addition to its effects on the blood vasculature (86).

Lymphatic vessels are involved in many physiological and pathological processes such as wound healing, chronic inflammation and tumor development (78). Inflammatory responses in tumors are associated with malignant progression and metastasis (87). Activated leukocytes in inflammatory sites produce a great number of growth factors including FGF, VEGF, and PDGF family members that might stimulate proliferation, migration and survival of isolated LECs. Macrophages have been shown to play a dual role in inflammation-induced lymphangiogenesis by secreting lymphangiogenic growth factors VEGF-C and -D that stimulate the growth of existing lymphatic endothelial cells and by trans-differentiating to lymphatic endothelial cells that incorporate into the lymphatic endothelium 88, 89, 90. In a mouse corneal wound model, Cursiefen et al. found that VEGF-A attracts macrophages to the injury site through activation of the VEGFR1 receptor, and then the activated inflammatory cells produce VEGF-C and VEGF-D to induce lymphangiogenesis (71). There is increasing evidence that lymphatic vessels also actively participate in acute and chronic inflammatory diseases. The chronic inflammatory skin disease psoriasis is characterized by pronounced cutaneous lymphatic hyperplasia, and chronic skin inflammation in mice is also associated with LEC proliferation and lymphatic hyperplasia (91). Furthermore, kidney transplant rejection is frequently accompanied by lymphangiogenesis (92), and these lymphatics produced the secondary lymphoid chemokine (SLC/CCL21), which further attracted CCR7+ lymphocytes and dendritic cells (89). Lymphangiogenesis has also been observed in experimental models of chronic airway inflammation (93). Recently, Kajiya et al. found that acute skin inflammation and edema formation induced by ultraviolet B (UVB) irradiation are associated with hyperpermeable, leaky lymphatic vessels that are functionally impaired (94). UVB irradiation of the skin also increases expression of VEGF-A, and systemic blockade of VEGF-A leads to diminished UVB-induced lymphatic vessel abnormalities and skin inflammation in mice (94). Halin et al. found that chronic inflammation actively induces lymphangiogenesis in LNs, which is controlled remotely by lymphangiogenic factors produced at the site of inflammation (95). Suppression of inflammatory cell numbers by bone marrow irradiation inhibits lymphangiogenesis in the cornea (71). COX-2 inhibitors and nonsteroidal, anti-inflammatory drugs were powerful inhibitors of lymphangiogenesis (42). Therefore, inhibition of inflammatory pathways may restrain lymphatic metastasis.

In many human cancers, the lymphatic vasculature represents the most important pathway for tumor cell dissemination. Recent discoveries have demonstrated the importance of tumor-associated lymphangiogenesis for the formation of lymph node metastases. Tumor-associated lymphangiogenesis has now been firmly established as a novel mechanism for cancer metastasis. Recent studies suggest that additional growth factors in addition to VEGF-C/VEGF-D/VEGFR-3 signaling axis are also involved in regulating lymphangiogenesis, and that there may be potential benefit in targeting of these growth factors in order to accomplish a complete blockade of lymphatic metastasis. The potential effects of most of these newly identified lymphatic growth factors on tumor-induced lymphangiogenesis and lymph node metastasis also remain to be further investigated. Despite the obvious promise of therapies targeted at tumor-induced lymphangiogenesis, a number of questions remain to be answered concerning the potential efficacy of targeting such lymphangiogenic growth factors in the management of cancer. The challenge for future studies is to identify new molecular players and increase our understanding of the basic biology of lymphatic development, which may open possibilities for novel therapeutic strategies for inhibiting tumor spread to lymph nodes.

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