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Clinical Updates

Sélim Aractingi, MD, PhD

Angiogenesis in Skin Malignancies

Selim Aractingi

Wednesday, January 16, 2013

Over the past 15 years, angiogenesis has been recognized as a major player in the behavior of many solid tumors. Indeed the growth of a cancer relies on the formation of blood vessels to ensure the supply of oxygen and nutrients. In addition, the metastatic process frequently relies on the development of lymphatic vessels, particularly in melanoma, cutaneous squamous cell carcinoma (SCC) and breast carcinoma. This opinion article will review the main data brought in this field and its potential consequences for the care and treatment of patients. 

A brief historical summary of angiogenesis in cancer

Angiogenesis occurs in adult tissues, where new blood vessels are formed out of existing vessels. This differs from vasculogenesis, which is only found during embryonic life. One of the first major studies that demonstrated the importance of angiogenesis in cancer came from transplantation of tumor specimens in the cornea of rabbits, an avascular area.1 The study showed that vessels grew from the limbus to reach the ectopic tumor. If capillaries were prevented in reaching the tumor, the tumor could not grow. Later on, several groups analyzed the temporal course of angiogenesis in solid tumors. This was done either in mice where a process of carcinogenesis has been induced or in specimens of various stages of human tumors. An angiogenic switch that becomes activated during the early stages of tumor development was found, suggesting that angiogenesis is a rate-limiting step in the pathway to solid cancers.2 This switch results from the favorable balance between inducers and inhibitors of angiogenesis. The secretion of inducers is usually made by the tumor cells themselves, while inhibitors are secreted by normal cells.2 However, there are situations in which a cell type that normally secretes an angiogenesis inhibitor stops this production; this is the case for fibroblasts mutated in p53 that lose their natural secretion of thrombospondin 1 (TSP1), an angiogenesis inhibitor.3 In recent decades, hundreds of studies have depicted the role of these molecules. Briefly, the main inducers of angiogenesis are the vascular endothelial growth factor (VEGF) family, the acidic fibroblast growth factor (aFGF) and the basic FGF (bFGF), while the major inhibitors are TSP1, angiostatin, platelet factor 4, and alpha-interferon.

The role of angiogenesis in melanoma

It was early noted that human melanoma grafted in the hamster cheek pouch induced angiogenesis in the tumor.4 But it was mainly at the end of the 80s/90s that dozens of studies were dedicated to assess the prognostic importance of vessels in primary melanoma. However, the initial results were contradictory, showing either a clear association between the metastatic risk and the vessel density - once the other parameters were adjusted - or in contrast, the absence of any link between them.5 These differences probably resulted from the differences in the techniques: the analysis could range from routine stains to computer quantitative measurements on sections labeled with antibodies, with some such as only factor VIII being able to stain part of immature intra-tumoral vessels.

Murine models were also used. These were engineered, allowing lymphatics to be specifically deleted or in contrast enhanced in skin. Without going into detail, it should be known that VEGFC and VEGFD are ligands, secreted by melanocytes (or macrophages in melanoma), able to selectively bind to VEGF receptor 3 (VEGFR3) on lymphatic endothelial cells. In mice, when malignant melanocytes were modified to overexpress one of these ligands, lymphangiogenesis was increased with an enhancement of lymph node metastasis.6,7 If VEGFA is overexpressed in the mice epidermis, melanoma dissemination to lymph nodes was also significantly increased.8

All these data indicate that tumor cells in melanoma induce the growth of lymphatic vessels, which promotes melanoma dissemination to lymph nodes. Surprisingly, studies in mice showed also that tumor-released VEGFA is transported by lymphatic vessels to the draining lymph nodes, where it induced lymphangiogenesis. This might prepare nodes for the future emigration of malignant cells.8

More recently, tools that allow us to discriminate between blood and lymphatic vessels in situhave been established. These rely on antibodies specific for each cell type such as CD34 and CD44 for blood vessels, and Lyve 1, Prox1, VEGFR3, podoplanin (D2/40) for lymphatics. Using these, several groups have measured the lymphatic surface in melanoma. Multivariate analyses have shown that tumor lymphangiogenesis was the most significant independent factor to predict positive sentinel lymph node biopsy.9 In the same way, the increase in melanoma lymphangiogenesis was found to inversely correlate with disease-free and overall survival in melanoma.10 Of note, VEGFC level correlated with lymphatic vessel density in melanoma.11 It has been shown also that lymphatic endothelial cells secrete the chemokines CCL21 and CXCL12 that bind to CCR7 and CXCR4 on malignant melanocytes, leading to chemoattraction and the promoting of metastasis of these cells.12 Thus a mutual crosstalk exists between melanocytes and lymphatics; the tumor cells secrete ligands such as VEGFC and VEGFD that induce lymphangiogenesis, while lymphatic endothelial cells attract malignant cells into their lumen. Finally, our group found that angiogenesis is enhanced in melanoma during pregnancy, such data indicate that gestation can influence cancer behavior through the modulation of vessels.13 

A future for antiangiogenic drugs in melanoma

As detailed above, blood and lymphatic vessel targeting should yield promising agents for the management of melanoma. A number of trials have evaluated bevacizumab, an anti-VEGFA antibody, in melanoma either as a single or multidrug regimen. However, a Phase III trial has yet to be reported. In a small non-comparative series, bevacizumab alone showed 31% response in melanoma.14 Other studies have added bevacizumab to classical protocols such as temozolomide, carboplatin/paclitaxel or fotemustine with typically small improvement. Sorafenib, a multikinase inhibitor, is efficient in inhibiting angiogenesis in liver and renal cell carcinoma. A Phase III trial evaluating the addition of sorafenib with carboplatin/paclitaxel has not shown improvement in efficacy.15 Despite these negative results, the prospect of future trials targeting lymphatic vessels more specifically, remains positive. Indeed, there are blocking antibodies or ligand traps for VEGFR3 and blockage of this pathway has shown efficiency in preclinical models.16 In addition, since the normal lymphatic vessels are usually quiescent in adults, this should constitute a safe target except for alterations in wound healing.

What about other skin malignancies?

Melanoma has been the main focus in the past decade concerning the investigations on tumor angiogenesis. However, it is noteworthy to mention here a major result in cutaneous squamous cell carcinoma (SCC). The two-step induced chemical carcinogenesis is a murine model where topically applying an initiator followed by a promoter leads to the development of papillomas (equivalent to pre-epitheliomatous keratosis) then of true SCC. It was previously shown in 1998 that adding VEGFA - through transgenesis - specifically to keratinocytes in these mice led to accelerated papilloma development and increased tumor burden.17 In these lesions, there is an increased cutaneous vascularization in the underlying dermis, indicating the importance of enhanced angiogenesis in epidermal cancers. However, recently, the group of Blanpain made an interesting and original finding. These authors used also the same murine model to analyze the features of cancer stem cells in skin SCC.18 They were first able to show that these cancer stem cells resided preferentially in a niche, in close physical contact with vessels, also demonstrating the importance of angiogenesis in SCC. Moreover, they were able to show through various techniques that these major cells were dependent for their maintenance on a molecular loop, though until now to interact in endothelial cells only (VEGFA/neuropilin 1). Briefly, Beck et al. demonstrated that the skin cancer stem cells secreted VEGFA that acted through an autocrine loop with neuropilin 1 also found in these cells. Therefore, VEGFA plays a dual role in SCC acting on vessels but also directly on cancer stem cells.

In summary, angiogenesis and lymphangiogenesis have major roles in melanoma and carcinoma development. The molecular players implicated have already been at least partly depicted. Despite the fact that current inhibitors have not yet been shown to be sufficiently active in melanoma, several groups are trying to go beyond these initial failures in order to help in the management of cutaneous malignancies.

Figure 1. Intratumoral CD31 vessels and D240 lymphatics in melanoma

Aractingi Fig 1


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