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14 December 2022

Renal Carcinoma and Angiogenesis: Therapeutic Target and Biomarkers of Response in Current Therapies

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and
1
Université Paris Cité, Inserm, PARCC, F-75015 Paris, France
2
Service d’Oncologie Médicale, AP-HP, Hôpital Européen Georges-Pompidou, F-75015 Paris, France
3
Service d’Hématologie Biologique, AP-HP, Hôpital Européen Georges-Pompidou, F-75015 Paris, France
*
Author to whom correspondence should be addressed.
Cancers2022, 14(24), 6167;https://doi.org/10.3390/cancers14246167
This article belongs to the Special Issue High Unmet Medical Needs in the Treatment of Renal Cell Carcinoma
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Simple Summary

The treatment of renal cancer is currently based on the use of antiangiogenic drugs targeting the VEGF-A pathway and/or immunotherapy targeting immune checkpoint inhibitors. Despite combined therapies being approved as first-line treatments, all patients will not benefit from them. We highlight here the role of tumour angiogenesis in renal cancer which makes angiogenesis-related markers good candidates to predict response to treatments including immunotherapies. Less data is available in this field for recently combined treatments. A combination of angiogenesis-related biomarkers with markers of other processes would be relevant to progress in the aim of personalized treatment.

Abstract

Due to the aberrant hypervascularization and the high immune infiltration of renal tumours, current therapeutic regimens of renal cell carcinoma (RCC) target angiogenic or immunosuppressive pathways or both. Tumour angiogenesis plays an essential role in tumour growth and immunosuppression. Indeed, the aberrant vasculature promotes hypoxia and can also exert immunosuppressive functions. In addition, pro-angiogenic factors, including VEGF-A, have an immunosuppressive action on immune cells. Despite the progress of treatments in RCC, there are still non responders or acquired resistance. Currently, no biomarkers are used in clinical practice to guide the choice between the different available treatments. Considering the role of angiogenesis in RCC, angiogenesis-related markers are interesting candidates. They have been studied in the response to antiangiogenic drugs (AA) and show interest in predicting the response. They have been less studied in immunotherapy alone or combined with AA. In this review, we will discuss the role of angiogenesis in tumour growth and immune escape and the place of angiogenesis-targeted biomarkers to predict response to current therapies in RCC.

1. Introduction

Renal cell carcinoma (RCC) represents 3 to 5% of all cancers in the world with an increasing incidence of approximately 400,000 cases in 2018 [1]. The predominant histological form is clear cell renal cell carcinoma (ccRCC) (>75%) and even today, the prognosis of this disease remains poor as 30% of patients have metastatic disease at diagnosis and the 5-year survival is estimated at 12% [2].
The development of new research tools has led to a better understanding of the biological and molecular mechanisms underlying the development of these cancers. Angiogenesis is required for tumour growth [3]. Indeed, tumour vessels bring oxygen and nutrients for tumour cells to survive and proliferate. Angiogenesis is also involved in tumour evasion from the immune system either directly or indirectly [4]. First, tumour vessels control immune cell infiltration. Second, abnormal tumour vascularization can promote hypoxia and many proangiogenic factors exert immunosuppressive functions. Angiogenesis is an even more important target in renal cancers because they present an aberrant angiogenesis and are resistant to chemo- and radiotherapy. Indeed, a very frequent mutation of the tumour suppressor gene VHL in ccRCC (>80% of cases) dysregulates hypoxia-inducing factor (HIF) inducing overexpression of vascular endothelial growth factor A (VEGF-A) and platelet-derived growth factor (PDGF) leading to tumour growth [5,6]. Tyrosine kinase inhibitors (TKIs) targeting the VEGF pathway have thus replaced IL-2 and IFN-α since 2005 [7,8].
Several years ago, the therapeutic arsenal was enriched with a new class of immunotherapy, immune checkpoint inhibitors (ICIs) targeting PD-1 or CTLA-4 [9,10]. Indeed, renal cancer is also one of the most immunogenic cancers with a tumour microenvironment (TME) characterized by an infiltration of various immune cells with an immunosuppressive phenotype [11]. Considering the link between angiogenesis and anti-tumour immunity, there is a strong rationale to combine ICI (anti-PD-1) with anti-angiogenic TKI [12]. Four combinations are currently approved for first-line treatment in m ccRCC (3 TKI-ICI-axitinib plus pembrolizumab, cabozantinib plus nivolumab and lenvatinib plus pembrolizumab—and 1 ICI-ICI-nivolumab plus ipilimumab) [13]. Despite ORRs ranging from 55% to 70% and a gain in PFS and OS, there are still patients who do not respond to these treatments, durable responses remain extremely rare, and progression is almost systematic. Biomarkers are therefore essential to target patients who could benefit from these treatments or to anticipate the occurrence of secondary resistance.
This review first describes angiogenesis and its role in tumour growth, particularly in renal cancer. To understand the importance of angiogenesis-related biomarkers to predict the response not only for anti-angiogenic TKI treatments, angiogenesis involvement in tumour immune escape is reported. We then review the interest in angiogenesis-related biomarkers to predict the response to TKI and recently available treatments. Whereas they have been extensively explored in the era of TKI treatments, biomarkers studied since the use of ICI were mostly related to immunity. They have proven to be useful in other cancers, but do not appear to predict responses in RCC [14,15]. The role of angiogenesis in predicting response to ICI or combination therapies remains to be clearly determined.

2. Methods

Angiogenesis being already well documented, we searched for English reviews from 2019 onwards as well as articles studying angiogenesis specifically in renal cancer. Concerning the part of the review focusing on angiogenesis biomarkers, the following literature search strategy was applied. We performed a systematic search on the PubMed bibliometric database including English-language articles published up to July 2022 reporting data relevant to biomarkers of current treatments, i.e., AA, ICI, or both in RCC patients. The following keywords were used: “renal carcinoma” “biomarker” “angiogenesis” or “VEGF”, « vessel », “immunotherapy”, and “combination”. Supplemental manual searches were conducted from congresses (2020–2022) of greatest relevance (the Annual Meeting of the American Society of Clinical Oncology [ASCO]; the ASCO Genitourinary Cancers Symposium [ASCO GU]; the Annual Meeting of the European Society for Medical Oncology [ESMO]). Some additional key articles that were published after the bibliometric search were identified by the authors and included. The objective of this part of the review was not to be exhaustive on anti-angiogenic TKI biomarkers, already highly described [16,17], but to report the mainly observed results and review the place of these angiogenesis-related biomarkers to predict response to recently used TKI, ICI, and combinations used in ccRCC.

3. Angiogenesis in Renal Cancer

3.1. Angiogenesis

Angiogenesis is one of the processes by which existing blood vessels form new ones [18]. This process is physiological and essential during embryonic life. It becomes quiescent during adult life except in certain conditions such as wound healing, ovarian cycle, or pregnancy. However, angiogenesis can be associated with pathological phenomena such as the development of cancers. Indeed, a tumour would not be able to measure more than 1 mm2 without the establishment of a vascular network allowing the supply of oxygen and nutrients [3].
Angiogenesis involves the development, migration, and proliferation of endothelial cells (EC) [18,19]. It is regulated by numerous pro- and anti-angiogenic factors. The main steps of angiogenesis are presented in Figure 1.
Figure 1. Regulation of angiogenesis. Quiescent ECs form a thin layer of single flat cells that line the interior surface of blood vessels and lymphatic vessels. These cells are interconnected by junctional molecules. EC monolayer is covered by pericytes, which control EC proliferation, release cell-survival signals and produce the basement membrane. ①. Hypoxia induces the secretion of pro-angiogenic factors. ②. This secretion leads to pericyte detachment, basement membrane degradation by metalloproteases and loss of EC junctions via VEGFR-2 activation. ③. One EC called tip cell is selected to guide elongation of the vessel towards proangiogenic signals. Remodeling of the existing matrix allows the migration of ECs. ④. Stalk cells proliferate and elongate to form a new vessel. ⑤. Following Dll4-Notch signaling and PDGF release, EC resume their quiescent state, the vessel is stabilized by recruitment of pericytes via PDGFR and deposition of a basement membrane. Adapted from “Tumor vascularization”, by BioRender.com (2022). Retrieved from https://app.biorender.com/biorender-templates (accessed on 4 December 2022).
Other processes of new vessel formation can be observed in tumours, such as vasculogenesis, co-option, or vascular mimicry [18]. Vasculogenesis relies on the recruitment of bone marrow-derived and/or vascular wall resident endothelial progenitor cells (EPCs) towards the tumour that differentiate into mature endothelial cells. Tumour cells can co-opt pre-existing vessels. Aggressive tumour cells can also form vessel-like structures without the contribution of endothelial cells. This mechanism, called vascular mimicry, has been seen in many cancers. Endothelial-like tumour cells express then endothelial markers such as CD31 [20,21]. This alternative neovascularization process adopted by the tumour may cope with the treatment and overcome the hypoxic environment [21].

3.2. Place of VEGF-A in Cancer Angiogenesis

3.2.1. Angiogenic Switch

VEGF-A is one of the most important factors in angiogenesis. It belongs to a family of 7 members: Placental Growth Factor (PlGF) 1 and 2, VEGF-B, VEGF-C, VEGF-D, and VEGF-E (a viral gene). While VEGF-A is a key regulator of angiogenesis, VEGF C, and D regulate lymphangiogenesis [22]. The effect of VEGF-A on ECs is mediated by intracellular signaling after binding to its receptors: VEGFR-1 and VEGFR-2. VEGFR-2 is the main signal transducer in angiogenesis, whereas VEGFR-1 plays a negative role in angiogenesis by maintaining an appropriate level of VEGFR-2 activation [23]. Signaling of VEGF-A through VEGFR-2 induces EC proliferation, migration, and increases vascular permeability and mobilization of endothelial progenitor cells (EPCs) [24]. Through VEGFR-1 binding, VEGF-A favors monocyte migration, allows the recruitment of EPCs, and increases the adhesive properties of NK cells. VEGFR-3, a receptor for VEGF-C is necessary for the formation of the blood vasculature during early embryogenesis, but later becomes a key regulator of lymphangiogenesis. Furthermore, NRP-1 and NRP-2 (neuropilins), better known for their role in neuronal development, are co-receptors for VEGFR-1 and 2 and increase the ligand affinity for these receptors suggesting a potential role in angiogenesis [24].
Hypoxia is a major factor driving angiogenesis. It decreases the degradation of the transcription factors HIF-α by ubiquitination and finally induces the expression of proangiogenic factors, among them VEGF-A (Figure 2). Contrary to HIF-1α which is a ccRCC suppressor, HIF-2α is a ccRCC oncoprotein and therefore an interesting therapeutic target already evaluated in several phase 2 that showed anti-tumour activity [25,26]. Phase 3 studies are ongoing to evaluate HIF-2α inhibitors as a single agent or in combination with immunotherapy (NCT03634540, NCT04736706). HIF-2α activates various genes encoding molecules that probably have a causal role in the development of ccRCC including angiogenic growth factors VEGF-A, PDGFB, and SDF-1 [27].
Figure 2. HIF Pathway. Under normoxic conditions, HIF-α is hydroxylated by prolyl hydroxylases (PHD) and then recognized by the VHL protein. Once VHL is bound to HIF-α, this leads to its ubiquitination and degradation by the proteasome. Under hypoxic conditions, HIF-α is not hydroxylized, accumulates in the cytosol, translocates to the nucleus and heterodimerizes with its subunit HIF-β. This leads to the transcription of genes with a hypoxia responsive element (HRE) in their promoter, responsible for cellular adaptation to hypoxia such as angiogenesis, survival, glucose metabolism and proliferation. Adapted from “HIF signalling”, by BioRender.com (2022). Retrieved from https://app.biorender.com/biorender-templates (accessed on 4 December 2022).
VEGF-A expression is also upregulated by growth factors, cytokines, and hormones such as estrogens [28]. In cancer, VEGF-A can be secreted by various types of cells following hypoxia: tumour cells mainly, but also fibroblasts, myeloid-derived stem cells, or NK cells [29]. VEGF-A production by tumour cells can also be due to oncogenic events. The disruption of the balance in favour of proangiogenic factors is essential for tumour growth and is called the “angiogenic switch”.

3.2.2. VHL and PBRM1 Inactivation in RCC

Clear cell RCC is usually associated with a mutation in the VHL gene. Mutations in VHL are either responsible for a loss of function or hypermethylation of the promoter making it non-functional. They can be somatic or secondary to a rare germline mutation leading to Von Hipple-Lindau disease which is responsible for a predisposition to certain types of hypervascular carcinoma such as ccRCC. Loss of function of VHL leads to an accumulation of HIF-α and mimics or aggravates a hypoxic situation in the tumour, leading to an increase in PI3-K/PKB/mTOR signalling and tumour progression [30,31].
VHL inactivation is usually the initiating event in the development of ccRCC. However, it is not sufficient to cause the occurrence of ccRCC, other cooperating genetic events are required, such as the loss of function of the tumour suppressor gene PBRM1. PBMR1 is the second most common gene mutated in ccRCC after VHL mutations. This gene encodes a component of a multiprotein SWI/SNF complex that regulates the position of nucleosomes in the genome [32]. PBRM1 knockdown increases the proliferation and migration of kidney cancer cell lines [33]. In addition, the loss of PBRM1 amplifies the transcriptional effects of HIF-1 and STAT3 caused by the loss of VHL [34]. Clinical studies have observed that alterations in PBRM1 are associated with increased expression of angiogenesis genes in ccRCC [35,36]. It, therefore, has an indirect role in tumour angiogenesis and is currently being studied extensively in ccRCC [36,37]. VHL-/- ccRCC tumours and cell lines produce both HIF-1α and HIF-2α or HIF-2α alone [38].

3.2.3. VEGF-A Promotes Immunosuppression

Tumour-induced angiogenesis is not only essential for tumour growth but also contributes to immune evasion through the induction of a highly immunosuppressive tumour microenvironment (TME). Excess of proangiogenic factors favours immunosuppression, both through their effects on tumour vasculature and immune cells (Figure 3).
Figure 3. Immunosuppression role of VEGF-A. Different immunosuppressive roles of angiogenesis are presented, either through the immunosuppressive functions of proangiogenic factors such as VEGF-A or through the immunosuppressive functions of the tumour blood vessels. a. illustrates the structure of normal blood vessels when activated with TNF-α which favours infiltration of immune cells, b. illustrates tumour blood vessels with altered structure and examples of immunosuppressive functions by expression of immunosuppressive molecules.
Mature vessels control many processes: vascular tone, permeability, inflammation, and coagulation [39]. Due to the imbalance in favour of proangiogenic factors, tumour vessels, unlike normal vessels, present abnormal characteristics. They are often immature, dilated, tortuous, disorganized, and therefore not fully functional [40]. They are also leaky, with poorly developed cell–cell contacts, and they display reduced pericyte coverage. Such aberrant tumour vessels can lead to a decrease in the supply of nutrients and oxygen and thus promote hypoxia in the TME which worsens tumour angiogenesis, immunosuppressive phenotype, and select resistant clones [41]). The increased permeability also facilitates tumour cell evasion. In the same tumour, vascularization can be heterogeneous with hypervascularized areas and others less. This also impacts the response to treatment.
Moreover, proangiogenic factors promote the creation of a selective immune-cell barrier [4,42]. Quiescent ECs control inflammation and limit access of leucocytes to the tissue [39]. When activated, ECs allow the recruitment and tissue infiltration of immune cells, particularly lymphocytes, to inflammatory sites through the expression of cell adhesion molecules such as ICAM-1 and VCAM-1. VEGF-A and bFGF, for example, decrease TNF-α induction of CAM expression by EC by blocking NFkB and inducing NO production [43]. Expression of molecules favouring the selective infiltration of immunosuppressive cells has also been reported, such as CLEVER-1, which promotes selective infiltration of regulatory T cells [44]. Fas-L expression induced by VEGF-A promotes a selective entry of regulatory T cells in the tumours owing to their higher expression of the anti-apoptotic factor c-FLIP, contrary to cytotoxic T cells [45]. It is interesting to notice that IFN-γ and TNF-α, important mediators of antitumour immune responses promoting PD-L1 and PD-L2 expression, inhibit tumour angiogenesis [46]. Under pro-inflammatory signals, EC can also present an immunosuppressive phenotype through the expression of immune checkpoints PD-L1 and PD-L2 or the production of immunosuppressive cytokines. Despite preclinical data in favour of an immunosuppressive role, the exact immunomodulatory role of ECs expressing PD-L1 or PD-L2 in tumours remains under investigation.
Proangiogenic factors involved in tumour angiogenesis can also promote immunosuppression by direct effects on immune cells. VEGF-A immunosuppressive role has been well described [47,48,49,50]. It inhibits the maturation of dendritic cells, with or without the help of NRP1, thus altering the presentation of tumour antigens. It favours the recruitment and proliferation of LTreg or other immunosuppressive cells such as MDSCs (myeloid-derived suppressor cells). Through its binding to VEGFR-2 expressed by CD8+ T cell, it increases the exhaustion of LT by promoting the expression of inhibitory checkpoint molecules such as PD-1, CTLA-4, LAG-3, and TIM-3. Similar immunosuppressive effects of other proangiogenic factors including hepatocyte growth factor (HGF), PDGF, and angiopoietins have also been reported [51].

3.3. Tumour Angiogenesis Contributes to Drug Resistance in RCC

3.3.1. Resistance to TKI

Mechanisms of resistance to AA and ICI rely on multiple pathways. The role of angiogenesis in tumour resistance to treatment has been largely reported for anti-angiogenic TKI used in monotherapy, such as sunitinib [52,53]. These mechanisms are either already present and explain primary resistance or can be induced secondary to TKI treatment.
Hypoxia-driven activation of other pro-angiogenic pathways inducing resistance has been reported. PDGFR, MET, AXL, and FGFR have been shown to play a role in resistance to VEGFR TKI [54,55]. Upregulation of PlGF (Placental growth factor) and angiopoietin 2 have also been described in ccRCC patients developing resistance to TKI [52,53]. These observations have guided the development of TKI targeting complementary pathways such as cabozantinib which inhibits c-Met [56] and lenvatinib which inhibits other FGFR [57]. Hypoxia also promotes the secretion of chemoattractants such as SDF-1 which recruits bone-marrow derived pro-angiogenic inflammatory cells in the TME.
Other mechanisms of resistance described for TKI include the metabolism adaptation of tumour cells to hypoxia, vascular co-option, epithelial-mesenchymal transition, lysosomal sequestration of the drug, epigenetic modification of histone protein and overexpression of PD-L1 [58,59]. Emerging evidence indicates that non-coding RNA such as micro RNAs (miRNA) or long non-coding RNAs (LncRNA) act as modulators of angiogenesis but not only and are involved in TKI resistance [60,61,62,63]. It might provide novel clinical markers and therapeutical targets for ccRCC patients, but due to their complex role and few data in ccRCC patients, at least for lncRNA, they will not be discussed further in this review.

3.3.2. Resistance to ICI

Inversely, the role of tumour angiogenesis in the resistance to ICI has been poorly studied. Resistance to ICI relies on an alteration of one of the following steps: antigen presentation and T cell priming, T cell infiltration in the tumour, and cytotoxic T cell activity in the tumour [58]. First, tumour vessels regulate T cell infiltration from peripheral blood into the tumour. Second, as explained previously, they can inactivate T cells by expressing checkpoint inhibitors or secreting immunosuppressive cytokines, like immune and tumour cells. Third, tumour hypoxia confers tumour cells resistance to both TKI and ICI and is usually associated with a bad prognosis [58]. Indeed, hypoxia promotes immunosuppression and tumour aggressiveness to survive in hypoxic areas. As explained previously, the importance and functionality of tumour angiogenesis regulate hypoxia in the tumour and are thus involved in the resistance to treatment. Angiogenesis biomarkers should thus be included in the biomarker studies performed in patients treated with immunotherapy.

5. Discussion

This review highlights the important role of angiogenesis not only in tumour development but also in the resistance to treatment, mainly through its interaction with hypoxia and immunity. Angiogenesis markers appear to be useful in predicting response to anti-VEGFR TKIs. Many studies have assessed circulating biomarkers of angiogenesis, particularly those related to the VEGF-A pathway in patients treated with sunitinib but few data are available in patients treated with ICI alone or combined with TKI. High VEGF-A level at baseline was consistently associated with worst outcomes in patients treated either with TKI or with ICI. Soluble VEGFR-2 blood level systematically decreases when patients are treated with TKI but only some studies report an association with the response to treatment. The study of other blood markers related to angiogenesis and their monitoring shows discordant results. Patient cohorts differ between studies leading to differences in baseline biomarker levels and thus in the threshold used to compare the outcomes of the patients. Standardization in the choice of threshold values is necessary to be able to validate and use blood biomarkers in clinical practice. Inconsistent results could also be partly explained by the diversity of angiogenic pathways that can be activated in the tumour or the involvement of other pathways. Concerning the tumour tissue biomarkers, the most advanced and reproducible results were obtained with the transcriptomic data thanks to currently available technologies. Several molecular signatures have been tested in patients treated with TKI or ICI alone or combined. Finally, several studies have shown evidence that upregulation of a set of angiogenesis-related genes seemed to help predict a better response to anti-VEGF therapy, whether alone or combined. Patients with low angiogenic tumour are less likely to respond to anti-VEGF therapy alone and may benefit more from strategies involving ICI. The study of other pathways than angiogenesis is needed to determine which patients among low angiogenic ones will benefit from the ICI TKI combination or would need other therapeutic options like the anti-HIF-2α belzutifan.
Both blood biomarkers and molecular signatures present strengths and weaknesses for use in clinical practice. Transcriptomic analysis has the advantage over blood biomarkers of targeting complementary pathways. However, this technique is expensive and tissue biopsy is required which limits its use to following the patients. Moreover, the accuracy of the result is limited by tumour heterogeneity. Blood biomarkers have the advantage of reflecting both primary tumour and metastatic lesions, but caution must be taken for their interpretation as it may also reflect the systemic reaction to treatment [142,143]. The main strength of blood biomarkers is their accessibility with a simple blood sampling allowing longitudinal follow-up. The value of monitoring over time has yet to be determined but could allow early detection of resistance or help to sequence combined therapies. For several years, the development of multiplexing technologies has allowed the quantification of many cytokines in a small blood volume. Thanks to that, the combination of blood biomarkers providing a circulating angiogenic profile could be tested. Combining angiogenesis and immune-related blood biomarkers would also allow us to have a more complete overview of the TME, as is the case for transcriptomic data.

6. Conclusions

The search for angiogenesis-related biomarkers is informative to guide therapeutic choice but also to get insight into the role of angiogenesis in resistance mechanisms. It is necessary to better understand mechanisms underlying resistance to treatments to determine potential new therapeutic targets or combinations. Ongoing studies are focusing on new therapeutic targets such as HIF combined or not with immunotherapy or even on treatment escalation with triple therapy trials (double immunotherapy-AA). Combinations need to be optimized concerning the timing and the dose. Therapies that can be used as subsequent-line treatment also need to be defined. In all these trials, the place of related-angiogenesis biomarkers should be assessed and combined with markers of other pathways. Finding biomarkers of interest could not only help clinicians in the choice of these different treatments but also allow de-escalation of therapy by proposing less burdensome treatments in patients with the best chance of responding.

Author Contributions

Conceptualization, Z.G. and L.M.; methodology, Z.G. and L.M.; validation, Z.G., M.A., Y.V., S.O., D.H. and L.M.; investigation, Z.G. and L.M.; writing—original draft preparation, Z.G., M.A., Y.V., S.O., D.H. and L.M.; writing—review and editing, Z.G., M.A., Y.V., S.O., D.H. and L.M. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Acknowledgments

All the figures were created with Biorender.com (accessed on 4 December 2022).

Conflicts of Interest

The authors declare no conflict of interest.

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