Prerpints.org logo
Preprint
Review

Predictive Value of Serum VEGF Levels in Non-Small Cell Lung Cancer: A Review

Altmetrics

Downloads

76

Views

41

Comments

0

Submitted:

18 September 2024

Posted:

19 September 2024

You are already at the latest version

Alerts
Abstract
Vascular endothelial growth factor (VEGF) and its receptors (VEGFRs) serve an essential role in tumor angiogenesis and have emerged as potential therapeutic targets in lung cancer. This review explores the significance of serum VEGF levels as a predictive biomarker in non-small cell lung cancer (NSCLC). The VEGF family, consisting of VEGFA, VEGFB, VEGFC, VEGFD, and placenta growth factor (PlGF), engages with specific receptors, including tyrosine kinase receptors (VEGFR-1, VEGFR-2, and VEGFR-3) and neuropilin receptors (NRP-1 and NRP-2), to promote angiogenesis and lymphangiogenesis. VEGF-A, the primary component of the VEGF family, binds to VEGFR-2 to stimulate endothelial cell proliferation and migration, while VEGF-B, VEGF-C, and VEGF-D interact with VEGFR-1 and VEGFR-3 to regulate tumor angiogenesis, lymphangiogenesis, and metastasis. The VEGF/VEGFR signaling pathway activates various downstream effectors, including phospholipase Cγ1, MAPK, and PI3K/Akt, which are essential for maintaining vascular homeostasis and promoting angiogenesis. In NSCLC, elevated serum VEGF levels have been observed, and the VEGF/VEGFR axis is frequently impaired, leading to irregular blood vessel formation and metastatic spread. Despite the development of anti-VEGF therapies, their impact on lung cancer outcomes has been limited. Further research is needed to optimize the effectiveness of these treatments and elucidate the potential of serum VEGF as a predictive biomarker in NSCLC.
Keywords: 
Subject: Medicine and Pharmacology  -   Oncology and Oncogenics

1. Introduction

Lung cancer is a significant contributor to cancer-related mortality in humanity. Due to its hostile nature, it is more often identified at a late stage and has an unfavorable prognosis. There are two main categories of lung cancer, non-small cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). NSCLC corresponds around 80-85% of cases, while SCLC, a more aggressive tumor, accounts for approximately 15% [1]. Survival rates has been increased due to systematic therapy, with the combination of programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) antibodies with platinum-doublet chemotherapy as the current standard of care for first-line treatment of advanced non-small-cell lung cancer (NSCLC) without a known targetable mutation regardless of PD-L1 score. Driver mutations like EGFR, KRAS, BRAF, and ALK were also detected, resulting in the development of targeted drugs. However, these medicines only provide advantages to certain groups of patients with specific molecular changes, and resistance mechanisms often restrict their effectiveness. This emphasizes the necessity for a more profound comprehension of the development of lung cancer and the discovery of novel targets for treatment [2].

2. Prospective Targeting of VEGF in Lung Cancer

Tumor angiogenesis, which involves the factors and signaling pathways, has emerged as a promising focus for therapeutic interventions in different malignancies, including lung cancer. VEGF and its receptors (VEGFRs) stimulate endothelial cell growth, movement, and infiltration via angiogenesis. VEGF promotes vascular permeability, aids in creating a temporary structure for the movement of endothelial cells and boosts the attraction of vascular precursor cells from the bone marrow. Recent research indicates that VEGF targets explicitly tumor cells, hence promoting the growth and spread of cancer. Both non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) patients have been found to have increased expression of vascular endothelial growth factor (VEGF) in the bloodstream. Despite multiple anti-VEGF medications that are now in clinical development or have already been approved, their impact on lung cancer outcomes has been limited, with only minor improvements observed compared to the encouraging preclinical results [2,3].

1. Overview of VEGF/VEGFR Axis

The Vascular Endothelial Growth Factor (VEGF) family, consisting of VEGFA, VEGFB, VEGFC, VEGFD, and placenta growth factor (PlGF), plays an integral part in the mechanism of angiogenesis. The functions of the members of the VEGF family are processed by the process of connecting with their particular receptors. VEGF receptors are classified into two types: tyrosine kinase receptors (VEGF receptors, VEGFR), consisting of VEGFR-1, VEGFR-2, and VEGFR-3, and neuropilin receptors (NRPs), which include NRP-1 and NRP-2 [4,5]. NRPs function as co-receptors for VEGF, and the connection between VEGF and NRPs enhances the stability of the receptor complex [4]. The members of the VEGF family exhibit a specific affinity for VEGFR. VEGF-A is the primary constituent of the VEGF family that promotes the formation of new blood vessels. It is present in all vascular tissues, macrophages, tumor cells, and other types of cells [6,7]. Furthermore, it can attach to both VEGFR-1 and VEGFR-2. Still, it mainly attaches to the latter to form a pair, self-phosphorylate, and activate, thereby playing a vital role in subsequent signaling processes. This leads to the growth and movement of endothelial cells and carries out duties related to forming new blood vessels. [8,9]. VEGF-B mainly attaches to VEGFR-1 and NRP-1 and significantly impacts tumor angiogenesis and the enhancement of ischemic damage situations [10,11]. VEGF-C and VEGF-D mostly attach to VEGFR-3 and contribute to the process of lymphangiogenesis [11,12]. VEGF-D is linked to the spread of tumors to nearby lymph nodes [13,14]. Additionally, PIGF primarily attaches to VEGFR-1 and controls the development and maturity of blood arteries by preventing the multiplication of endothelial and parietal cells [15].
VEGFR-1 is expressed in numerous cell types other than endothelial cells and has an important function in regulating leukocyte migration. VEGFRs consist of seven immunoglobulin (Ig) homology regions which contain the area where the ligand binds. Additionally, they have an intracellular domain that exhibits tyrosine kinase activity, which is responsible for transmitting signals within the cell. VEGF contact induces the activation of phospholipase Cγ1, the MAPK pathway via Ras/Raf1 activation, and the PI3K/Akt pathway. Phospholipase Cγ1 holds a critical role in controlling the concentration of Ca+2 ions within cells and the production of endothelial nitric oxide synthase. The collective impact of these series of events is crucial for preserving the fundamental stability of blood vessels and facilitating processes such as the formation of new blood vessels, cell division, and migration of cells. The VEGF/VEGFR signaling system is frequently altered in several cancer types, which results in the formation of malformed blood vessels and the spreading of metastatic cancer cells [16,17].

2. Role of VEGF in Angiogenesis and Cancer

Several proteins and genes that play a crucial role in controlling the cell cycle, angiogenesis, and apoptosis have been identified as markers that greatly influence the response to treatment and clinical prognosis in patients with non-small cell lung cancer (NSCLC) [18,19]. Angiogenesis is a vital factor for the proliferation and metastasis of tumors and has been found to be a separate prognostic factor [20]. VEGF is a crucial and significant activator of tumor angiogenesis. Among the conflicting influences of proangiogenic and antiangiogenic factors, a signal appears that stimulates the generation of Vascular Endothelial Growth Factor (VEGF). This specific signaling system enables VEGF to perform many effects in the process of neoangiogenesis. VEGF expression mostly appears in endothelial cells, but it has also been detected at high levels in several types of tumors, including lung tumor cells. Hypoxia produces increased levels of VEGF in tumor tissue and stabilizes and enhances the expression of the transcription factor HIF-1α (Hypoxia-inducible factor-1α). HIF-1α, in turn, promotes the transcription of VEGF, which is then released, diffuses through the tissue, and binds to specific receptors on the surface of endothelial cells. Several studies indicate a correlation between the genetic variation of VEGF and the sensitivity, prognosis, and therapeutic responsiveness of individuals with NSCLC [21].

3. Role of VEGF in the Procedures of TME Cell Components in NSCLC

According to studies VEGF plays a role in malignancies by inducing the growth of new blood vessels (angiogenesis), but also by affecting tumor cells [22]. VEGF may stimulate the formation and spread of tumors by binding to receptors found on tumor cells through autocrine and paracrine processes [23]. NRPs, together with tyrosine kinases, have the ability to control the activity and motion of growth factor receptors and integrins. This makes them essential in aiding the effects of VEGF on malignant cells [23]. Malignant cells evade the immune response by inhibiting the function of T cells, such as by elevating the levels of T cell checkpoints [24,25]. VEGF-A promotes the production of PD-1 and other suppressive checkpoints, like CTLA-4, on the surface of T cells. Moreover, it impedes the operation of CD8+ T cells, resulting in a persistent malfunction that ultimately hinders the effector role of T cells [26,27]. Recent research indicates that tumor hypoxia, angiogenesis, and immunosuppression could mutually disrupt each other, fostering tumor progression and reducing the efficacy of cancer therapy [28]. VEGF not only directly modulates T cell activity but also potentially suppresses T cell function by regulating the levels of Fas ligand (FasL). VEGF-A amplifies the presence of FasL in the tumor microenvironment (TME) [29,30]. FasL is present in the outer layer of T cells and in cancer endothelial cells, while being absent in a healthy vascular system. The presence of FasL in endothelial cells in human carcinomas leads to the reduction of CD8+ T lymphocytes [31,32]. Regulatory T cells, often called Treg cells, are an essential group of CD4+ T cells. Various preclinical and clinical studies have shown that Treg cells are a predominant kind of immunosuppressive cells observed in malignancies [32]. They inhibit the process of immune surveillance to counteract cancer in individuals with favorable medical conditions. They impede the ability of patients with tumors to develop anti-tumor solid immunity, which leads to the formation and advancement of different types of malignant tumors, such as NSCLC [33]. The expression of VEGF-A in cancer patients was found to relate strongly with the levels of intratumoral Tregs [34]. VEGF-A can promote the development of regulatory T cells (Tregs) by increasing the population of immature dendritic cells (DCs) [35]. In addition, VEGF-A can directly control the recruitment of Treg cells in the tumor microenvironment (TME) by binding to VEGFR2. This interaction boosts the proliferation of Treg cells and enhances their immunosuppressive activity [32,35,36]. Tumor-associated macrophages (TAMs) are versatile cells that can adopt various polarization states. They play a crucial role in the initiation and advancement of cancer [37]. Tumor-associated macrophages (TAMs) are found at every stage of tumor formation, making them the most prevalent immune cells in the tumor microenvironment (TEM) [38]. There are two distinct phenotypes of TAMs, namely M1 and M2. The M1 phenotype has tumor-suppressing actions, while the M2 phenotype facilitates tumor advancement [39]. Tumor-associated macrophages (TAMs) produce cytokines, chemokines and growth factors that induce immunosuppression, and activate the suppressive immunological checkpoint proteins in T cells [40]. Hwang et al. demonstrated that M2 tumor-associated macrophages (TAMs) significantly increased VEGF-A and VEGF-C expression levels in non-small cell lung cancer (NSCLC) cells. On the other hand, M1 TAMs only increased the expression levels of VEGF-A in NSCLC cells. This indicates that TAMs play a significant role in the development of blood vessels and lymphatic vessel formation, promoting the advancement of NSCLC [41].
A type of cell called dendritic cells has the highest potential to present antigens compared to other cells. They can produce cytokines and facilitate the development of effector T and NK cells [42,43]. Dendritic cells (DC) can be separated from the first phase of hematopoietic progenitor cell (HPC) and VEGF-A may contribute to this mechanism by binding to HPC CD34+ cells through VEGFR-1 and thus suppressing the activity of nuclear factor-κB (NF-κB), that activates transcription factors in these cells. As a result, the differentiation and maturation of DC are inhibited [44,45]. VEGF can potentially hinder the function of dendritic cells by increasing the expression of PD-1. Blocking the development of dendritic cells decreases the infiltration of T cells into tumors and has an immunosuppressive impact. Recent data reveal that VEGF might impair mature DCs’ migratory ability and immunological activity through the VEGFR-2-mediated RhoA-cofilin1 pathway [46].
Elevated levels of immature DCs in cancer patients are correlated with heightened levels of VEGF, which play a role in facilitating the malfunction of DCs [44]. In addition, the findings of a clinical trial examining the connection between DC infiltration and VEGF expression in NSCLC (132 primary NSCLC patients who underwent surgery) revealed that the average number of infiltrating DCs in the group with high VEGF expression was lower than that in the group with low expression [47]. This suggests that VEGF might control the infiltration of DCs into NSCLC tumors.
VEGF-A is a factor that can enhance the proliferation of myeloid-derived suppressor cells (MDSCs). The MDSC population comprises diverse and varied immature myeloid cells, which serve as progenitor cells for macrophages, dendritic cells (DC), or granulocytes. MDSCs are defined by their origin in the bone marrow, immature state, and ability to suppress the immune response [48]. These factors can enhance the survival of tumor cells, stimulate the growth of new blood vessels (angiogenesis), facilitate the invasion of tumor cells, and accelerate the spread of cancer to other parts of the body (metastases). In addition, MDSCs can promote immunological tolerance and decrease the activity of effector T cells and NK cells, hence stimulating immune responses [48,49]. Furthermore, MDSCs can hinder the proliferation of T cells specific to tumors and facilitate the formation of regulatory T cells (Tregs), which are crucial in suppressing the immune response and evading the immune system. MDSCs are also implicated in the process of Treg cell development. An elevation of myeloid-derived suppressor cells (MDSC) in the bloodstream of individuals with cancer leads to a reduction in the number of fully developed dendritic cells (DCs) [50]. Many studies have indicated that MDSCs play a significant role in modulating a range of tumor-related immunosuppressive activities and tumor immune escape, including NSCLC [32].
Natural Killer (NK) cells are a specific subset of cytotoxic innate lymphoid cells within the innate immune system. They possess a distinct ability to eliminate tumor cells effectively. VEGF can impede the development of NK cells by obstructing the maturation of DCs [44,51]. In addition, VEGF can enhance the quantity of MDSCs and suppress the activity of NK cells, resulting in immunological escape [32].
Research has demonstrated that natural killer (NK) cells are capable of releasing vascular endothelial growth factor-A (VEGF-A) when exposed to low oxygen circumstances, which is a distinguishing feature of the tumor microenvironment (TME) [52]. In settings of low oxygen levels (hypoxia), the release of VEGF is temporary. This is because when NK cells return to the bloodstream, this occurrence can be reversed. Hypoxia plays an essential part during cancer treatment by causing an imbalance in the signaling between pro- and antiangiogenic variables and physical compression. This results in abnormal blood vessels and substantially decreased blood flow in tumors. The increasing heterogeneity in blood flow, which worsens over time, differs depending on the stage and location of tumor growth. This leads to cancer cells evading the immune system, enhancing their ability to move in and spread to other body parts, and exerting selected survival pressures. By relieving hypoxia, it is possible to alter the characteristics of macrophages, making them more supportive of tumor growth and suppressing the immune response, improving the efficiency of cancer treatment [53].

4. VEGF and Immune Checkpoints in NSCLC

VEGF not only stimulates tumor growth by facilitating the formation of new blood vessels but also affects different immune cells in the tumor microenvironment, suppressing the immune response. Thus, while treating NSCLC, choosing VEGF-VEGFR-targeted medications can impede tumor growth.
VEGF is upregulated in non-small cell lung cancer (NSCLC), with higher expression levels observed in the tumor tissue compared to the adjacent normal lung tissue [54]. The elevated Vascular Endothelial Growth Factor (VEGF) expression is associated with tumor recurrence, reduced survival rate, metastasis, and mortality [54,55]. VEGF is essential for tumor progression and immunosuppression. Hence, specific medications that hinder the VEGF pathway, such as monoclonal antibodies against VEGF and tyrosine kinase inhibitors (TKIs), are employed to treat NSCLC.
An immunological checkpoint is a protein that can induce immunosuppression, hence modulating the immune response. Monoclonal antibodies that inhibit the binding of cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death protein (PD-1) or its ligand PD-L1 have received clinical approval. PD-1 and PD-L1 are predominantly present in immune cells, specifically NK cells, DC, CD4+, and CD8+ T cells [56,57]. PD-1 binds with its ligand PD-L1 to suppress the activation and reproduction of T cells, resulting in the evasion of the immune system. Strong connections were found between the levels of PD-L1 expression and the levels of angiogenic factors, including VEGFA and HIF-1α [58]. CTLA-4 is an external protein found on the surface of cells that can regulate immunological suppression. Its primary function is to activate T cell receptors, which play a crucial role in the immune response [59].
The first-line therapy, now approved as immune checkpoint inhibitors, can be classified into three primary categories: Anti-PD-1, Anti-PD-L1, and Anti-CTLA-4. VEGF-A suppresses immune activation and promotes immunosuppression by influencing different immune cells inside the tumor microenvironment (TME). Thus, the suppression of immunological escape can be achieved by decreasing the impact of VEGF, followed by the combination of immune checkpoint inhibitors for the treatment of NSCLC. Initially, anti-angiogenic medications have the ability to restore normalcy to the blood vessels within tumors, resulting in an increase of tumor immune cells, specifically tumor-infiltrating lymphocytes, in cases of non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors alleviate the suppression of PD-1 and PD-L1 on T cells, and the combined impact of these two factors result in improved treatment outcomes for solid malignancies [60].
A restricted number of studies have investigated the importance of plasma vascular endothelial growth factor (VEGF) levels in predicting the therapeutic outcomes of anti-angiogenesis together with anti-PD-L1 approaches. Tozuka et al. indicated that patients who had a reduction in their post-treatment plasma VEGF-A concentrations in comparison to their pre-treatment levels exhibited a markedly extended progression-free survival (PFS) in contrast to those whose post-treatment plasma VEGF-A concentrations either increased or remained stable. Within the responder cohort, a larger fraction of patients demonstrated a persistent decline in their plasma VEGF-A levels across the treatment period [61].

4. Discussion

Vascular endothelial growth factor (VEGF) facilitates tumor proliferation by enabling the formation of new blood vessels and controls various immune cells inside the tumor microenvironment, therefore inhibiting immune response. Upregulation of VEGF in non-small cell lung cancer (NSCLC) is linked to increased expression levels, which in turn are connected with tumor recurrence, decreased survival rate, metastasis, and death. Monoclonal antibodies targeting VEGF and tyrosine kinase inhibitors (TKIs) are drug therapies used to treat non-small cell lung cancer (NSCLC) by inhibiting the VEGF transport route. Levels of plasma vascular endothelial growth factor (VEGF) have been shown to indicate the effectiveness of anti-angiogenesis and anti-PD-L1 therapies. Significantly prolonged progression-free survival (PFS) was seen in patients with decreased post-treatment plasma VEGF-A levels. Further studies are needed for the evaluation of different VEGF factors and their potential roles as prognostic and predictive factors for NSCLC.

Author Contributions

“Conceptualization, E.K.; methodology, E.K.; resources, E.K., N.S; writing—original draft preparation, E.K.; writing—review and editing, E.K., N.S.; supervision, A.C.; project administration, E.K. All authors have read and agreed to the published version of the manuscript.”

Funding

“This research received no external funding”

Conflicts of Interest

“The authors declare no conflicts of interest.”

References

  1. Johnson, D. H., Schiller, J. H., & Bunn, P. A. (2014). Recent Clinical Advances in Lung Cancer Management. Journal of Clinical Oncology, 32(10), 973–982. [CrossRef]
  2. Zhao, Y., & Adjei, A. A. (2015). Targeting Angiogenesis in Cancer Therapy: Moving Beyond Vascular Endothelial Growth Factor. The Oncologist, 20(6), 660–673. [CrossRef]
  3. Jayson, G. C., Kerbel, R., Ellis, L. M., & Harris, A. L. (2016). Antiangiogenic therapy in oncology: current status and future directions. The Lancet, 388(10043), 518–529. [CrossRef]
  4. Weddell, J. C., Chen, S., & Imoukhuede, P. I. (2017). VEGFR1 promotes cell migration and proliferation through PLCγ and PI3K pathways. Npj Systems Biology and Applications, 4(1), 1-11. [CrossRef]
  5. Ceci, C., Atzori, M. G., Lacal, P. M., & Graziani, G. (2020). Role of VEGFs/VEGFR-1 Signaling and Its Inhibition in Modulating Tumor Invasion: Experimental Evidence in Different Metastatic Cancer Models. International Journal of Molecular Sciences, 21(4), 1388. [CrossRef]
  6. Zachary, I. (2003). VEGF signalling: integration and multi-tasking in endothelial cell biology. Biochemical Society Transactions, 31(6), 1171–1177. [CrossRef]
  7. Lal BK, Varma S, Pappas PJ, Hobson RW 2nd, Durán WN. VEGF increases permeability of the endothelial cell monolayer by activation of PKB/akt, endothelial nitric-oxide synthase, and MAP kinase pathways. Microvasc Res. 2001 Nov;62(3):252-62. PMID: 11678628. [CrossRef]
  8. Graupera M, Potente M. Regulation of angiogenesis by PI3K signaling networks. Exp Cell Res. 2013 May 15;319(9):1348-55. Epub 2013 Mar 13. PMID: 23500680. [CrossRef]
  9. Qi, J. H., & Claesson-Welsh, L. (2001). VEGF-Induced Activation of Phosphoinositide 3-Kinase Is Dependent on Focal Adhesion Kinase. Experimental Cell Research, 263(1), 173-182. [CrossRef]
  10. Ugurel, S., Rappl, G., Tilgen, W., & Reinhold, U. (2001). Increased Serum Concentration of Angiogenic Factors in Malignant Melanoma Patients Correlates With Tumor Progression and Survival. Journal of Clinical Oncology, 19(2), 577–583. [CrossRef]
  11. Claffey KP, Brown LF, del Aguila LF, Tognazzi K, Yeo KT, Manseau EJ, Dvorak HF. Expression of vascular permeability factor/vascular endothelial growth factor by melanoma cells increases tumor growth, angiogenesis, and experimental metastasis. Cancer Res. 1996 Jan 1;56(1):172-81. PMID: 8548760.
  12. Jinnin, M., Medici, D., Park, L., Limaye, N., Liu, Y., Boscolo, E., Bischoff, J., Vikkula, M., Boye, E., & Olsen, B. R. (2008). Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma. Nature Medicine, 14(11), 1236-1246. [CrossRef]
  13. Marasco LE, Kornblihtt AR. The physiology of alternative splicing. Nat Rev Mol Cell Biol. 2023 Apr;24(4):242-254. Epub 2022 Oct 13. PMID: 36229538. [CrossRef]
  14. Wang J, Wang C, Li L, Yang L, Wang S, Ning X, Gao S, Ren L, Chaulagain A, Tang J, Wang T. Alternative splicing: An important regulatory mechanism in colorectal carcinoma. Mol Carcinog. 2021 Apr;60(4):279-293. Epub 2021 Feb 25. PMID: 33629774. [CrossRef]
  15. Mehterov N, Kazakova M, Sbirkov Y, Vladimirov B, Belev N, Yaneva G, Todorova K, Hayrabedyan S, Sarafian V. Alternative RNA Splicing-The Trojan Horse of Cancer Cells in Chemotherapy. Genes (Basel). 2021 Jul 18;12(7):1085. PMID: 34356101; PMCID: PMC8306420. [CrossRef]
  16. Mabeta, P., & Steenkamp, V. (2022). The VEGF/VEGFR Axis Revisited: Implications for Cancer Therapy. International Journal of Molecular Sciences, 23(24), 15585. [CrossRef]
  17. Ribatti, D. (2022). Immunosuppressive effects of vascular endothelial growth factor (Review). Oncology Letters, 24(4). [CrossRef]
  18. Guimarães-Bastos D, Frony AC, Barja-Fidalgo C, Moraes JA. Melanoma-derived extracellular vesicles skew neutrophils into a pro-tumor phenotype. J Leukoc Biol. 2022 Mar;111(3):585-596. Epub 2021 May 27. PMID: 34043843. [CrossRef]
  19. McHale C, Mohammed Z, Gomez G. Human Skin-Derived Mast Cells Spontaneously Secrete Several Angiogenesis-Related Factors. Front Immunol. 2019 Jun 25;10:1445. PMID: 31293594; PMCID: PMC6603178. [CrossRef]
  20. Sammarco G, Varricchi G, Ferraro V, Ammendola M, De Fazio M, Altomare DF, Luposella M, Maltese L, Currò G, Marone G, Ranieri G, Memeo R. Mast Cells, Angiogenesis and Lymphangiogenesis in Human Gastric Cancer. Int J Mol Sci. 2019 Apr 29;20(9):2106. PMID: 31035644; PMCID: PMC6540185. [CrossRef]
  21. Zhao, Y., Guo, S., Deng, J., Shen, J., Du, F., Wu, X., Chen, Y., Li, M., Chen, M., Li, X., Li, W., Gu, L., Sun, Y., Wen, Q., Li, J., & Xiao, Z. (2022). VEGF/VEGFR-Targeted Therapy and Immunotherapy in Non-small Cell Lung Cancer: Targeting the Tumor Microenvironment. International Journal of Biological Sciences, 18(9), 3845–3858. [CrossRef]
  22. Frezzetti D, Gallo M, Maiello MR, D’Alessio A, Esposito C, Chicchinelli N, Normanno N, De Luca A. VEGF as a potential target in lung cancer. Expert Opin Ther Targets. 2017 Oct;21(10):959-966. Epub 2017 Aug 30. PMID: 28831824. [CrossRef]
  23. Goel HL, Mercurio AM. VEGF targets the tumour cell. Nat Rev Cancer. 2013 Dec;13(12):871-82. PMID: 24263190; PMCID: PMC4011842. [CrossRef]
  24. Lei X, Lei Y, Li JK, Du WX, Li RG, Yang J, Li J, Li F, Tan HB. Immune cells within the tumor microenvironment: Biological functions and roles in cancer immunotherapy. Cancer Lett. 2020 Feb 1;470:126-133. Epub 2019 Nov 12. PMID: 31730903. [CrossRef]
  25. Galassi C, Musella M, Manduca N, Maccafeo E, Sistigu A. The Immune Privilege of Cancer Stem Cells: A Key to Understanding Tumor Immune Escape and Therapy Failure. Cells. 2021 Sep 8;10(9):2361. PMID: 34572009; PMCID: PMC8469208. [CrossRef]
  26. Voron T, Colussi O, Marcheteau E, Pernot S, Nizard M, Pointet AL, Latreche S, Bergaya S, Benhamouda N, Tanchot C, Stockmann C, Combe P, Berger A, Zinzindohoue F, Yagita H, Tartour E, Taieb J, Terme M. VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. J Exp Med. 2015 Feb 9;212(2):139-48. Epub 2015 Jan 19. PMID: 25601652; PMCID: PMC4322048. [CrossRef]
  27. de Almeida PE, Mak J, Hernandez G, Jesudason R, Herault A, Javinal V, Borneo J, Kim JM, Walsh KB. Anti-VEGF Treatment Enhances CD8+ T-cell Antitumor Activity by Amplifying Hypoxia. Cancer Immunol Res. 2020 Jun;8(6):806-818. Epub 2020 Apr 1. PMID: 32238381. [CrossRef]
  28. Zhang, L., Zhang, B., Li, L., Ye, Y., Wu, Y., Yuan, Q., Xu, W., Wen, X., Guo, X., & Nian, S. (2022b). Novel targets for immunotherapy associated with exhausted CD8 + T cells in cancer. Journal of Cancer Research and Clinical Oncology, 149(5), 2243–2258. [CrossRef]
  29. Lu, L., Zhang, Y., Tan, X., Merkher, Y., Leonov, S., Zhu, L., Deng, Y., Zhang, H., Zhu, D., Tan, Y., Fu, Y., Liu, T., & Chen, Y. (2022). Emerging mechanisms of pyroptosis and its therapeutic strategy in cancer. Cell Death Discovery, 8(1). [CrossRef]
  30. Flores-Mendoza G, Rodríguez-Rodríguez N, Rubio RM, Madera-Salcedo IK, Rosetti F, Crispín JC. Fas/FasL Signaling Regulates CD8 Expression During Exposure to Self-Antigens. Front Immunol. 2021 Mar 24;12:635862. PMID: 33841416; PMCID: PMC8024570. [CrossRef]
  31. Ohm JE, Gabrilovich DI, Sempowski GD, Kisseleva E, Parman KS, Nadaf S, Carbone DP. VEGF inhibits T-cell development and may contribute to tumor-induced immune suppression. Blood. 2003 Jun 15;101(12):4878-86. Epub 2003 Feb 13. PMID: 12586633. [CrossRef]
  32. Zhao, Y., Guo, S., Deng, J., Shen, J., Du, F., Wu, X., Chen, Y., Li, M., Chen, M., Li, X., Li, W., Gu, L., Sun, Y., Wen, Q., Li, J., & Xiao, Z. (2022b). VEGF/VEGFR-Targeted Therapy and Immunotherapy in Non-small Cell Lung Cancer: Targeting the Tumor Microenvironment. International Journal of Biological Sciences, 18(9), 3845–3858. [CrossRef]
  33. Tanaka A, Sakaguchi S. Regulatory T cells in cancer immunotherapy. Cell Res. 2017 Jan;27(1):109-118. Epub 2016 Dec 20. PMID: 27995907; PMCID: PMC5223231. [CrossRef]
  34. Sun L, Xu G, Liao W, Yang H, Xu H, Du S, Zhao H, Lu X, Sang X, Mao Y. Clinicopathologic and prognostic significance of regulatory T cells in patients with hepatocellular carcinoma: a meta-analysis. Oncotarget. 2017 Jun 13;8(24):39658-39672. PMID: 28487498; PMCID: PMC5503641. [CrossRef]
  35. Bourhis M, Palle J, Galy-Fauroux I, Terme M. Direct and Indirect Modulation of T Cells by VEGF-A Counteracted by Anti-Angiogenic Treatment. Front Immunol. 2021 Mar 29;12:616837. PMID: 33854498; PMCID: PMC8039365. [CrossRef]
  36. Fukumura D, Kloepper J, Amoozgar Z, Duda DG, Jain RK. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat Rev Clin Oncol. 2018 May;15(5):325-340. Epub 2018 Mar 6. PMID: 29508855; PMCID: PMC5921900. [CrossRef]
  37. Zhou K, Cheng T, Zhan J, Peng X, Zhang Y, Wen J, Chen X, Ying M. Targeting tumor-associated macrophages in the tumor microenvironment. Oncol Lett. 2020 Nov;20(5):234. Epub 2020 Sep 14. PMID: 32968456; PMCID: PMC7500051. [CrossRef]
  38. Vitale I, Manic G, Coussens LM, Kroemer G, Galluzzi L. Macrophages and Metabolism in the Tumor Microenvironment. Cell Metab. 2019 Jul 2;30(1):36-50. PMID: 31269428. [CrossRef]
  39. Myers KV, Amend SR, Pienta KJ. Targeting Tyro3, Axl and MerTK (TAM receptors): implications for macrophages in the tumor microenvironment. Mol Cancer. 2019 May 14;18(1):94. PMID: 31088471; PMCID: PMC6515593. [CrossRef]
  40. Lin Y, Xu J, Lan H. Tumor-associated macrophages in tumor metastasis: biological roles and clinical therapeutic applications. J Hematol Oncol. 2019 Jul 12;12(1):76. PMID: 31300030; PMCID: PMC6626377. [CrossRef]
  41. Hwang I, Kim JW, Ylaya K, Chung EJ, Kitano H, Perry C, Hanaoka J, Fukuoka J, Chung JY, Hewitt SM. Tumor-associated macrophage, angiogenesis and lymphangiogenesis markers predict prognosis of non-small cell lung cancer patients. J Transl Med. 2020 Nov 23;18(1):443. PMID: 33228719; PMCID: PMC7686699. [CrossRef]
  42. Bosch NC, Voll RE, Voskens CJ, Gross S, Seliger B, Schuler G, Schaft N, Dörrie J. NF-κB activation triggers NK-cell stimulation by monocyte-derived dendritic cells. Ther Adv Med Oncol. 2019 Dec 11;11:1758835919891622. PMID: 31853267; PMCID: PMC6909276. [CrossRef]
  43. Lucarini V, Melaiu O, Tempora P, D’Amico S, Locatelli F, Fruci D. Dendritic Cells: Behind the Scenes of T-Cell Infiltration into the Tumor Microenvironment. Cancers (Basel). 2021 Jan 23;13(3):433. PMID: 33498755; PMCID: PMC7865357. [CrossRef]
  44. Han Z, Dong Y, Lu J, Yang F, Zheng Y, Yang H. Role of hypoxia in inhibiting dendritic cells by VEGF signaling in tumor microenvironments: mechanism and application. Am J Cancer Res. 2021 Aug 15;11(8):3777-3793. PMID: 34522449; PMCID: PMC8414384.
  45. Khan KA, Kerbel RS. Improving immunotherapy outcomes with anti-angiogenic treatments and vice versa. Nat Rev Clin Oncol. 2018 May;15(5):310-324. Epub 2018 Feb 13. PMID: 29434333. [CrossRef]
  46. Long J, Hu Z, Xue H, Wang Y, Chen J, Tang F, Zhou J, Liu L, Qiu W, Zhang S, Ouyang Y, Ye Y, Xu G, Li L, Zeng Z. Vascular endothelial growth factor (VEGF) impairs the motility and immune function of human mature dendritic cells through the VEGF receptor 2-RhoA-cofilin1 pathway. Cancer Sci. 2019 Aug;110(8):2357-2367. Epub 2019 Jun 28. PMID: 31169331; PMCID: PMC6676124. [CrossRef]
  47. Inoshima N, Nakanishi Y, Minami T, Izumi M, Takayama K, Yoshino I, Hara N. The influence of dendritic cell infiltration and vascular endothelial growth factor expression on the prognosis of non-small cell lung cancer. Clin Cancer Res. 2002 Nov;8(11):3480-6. PMID: 12429638.
  48. Hegde S, Leader AM, Merad M. MDSC: Markers, development, states, and unaddressed complexity. Immunity. 2021 May 11;54(5):875-884. PMID: 33979585; PMCID: PMC8709560. [CrossRef]
  49. Weber R, Groth C, Lasser S, Arkhypov I, Petrova V, Altevogt P, Utikal J, Umansky V. IL-6 as a major regulator of MDSC activity and possible target for cancer immunotherapy. Cell Immunol. 2021 Jan;359:104254. Epub 2020 Nov 29. PMID: 33296753. [CrossRef]
  50. Almand B, Resser JR, Lindman B, Nadaf S, Clark JI, Kwon ED, Carbone DP, Gabrilovich DI. Clinical significance of defective dendritic cell differentiation in cancer. Clin Cancer Res. 2000 May;6(5):1755-66. PMID: 10815894.
  51. Wang L, Dai Y, Zhu F, Qiu Z, Wang Y, Hu Y. Efficacy of DC-CIK-based immunotherapy combined with chemotherapy in the treatment of intermediate to advanced non-small cell lung cancer. Am J Transl Res. 2021 Nov 15;13(11):13076-13083. PMID: 34956526; PMCID: PMC8661198.
  52. Hawke LG, Whitford MKM, Ormiston ML. The Production of Pro-angiogenic VEGF-A Isoforms by Hypoxic Human NK Cells Is Independent of Their TGF-β-Mediated Conversion to an ILC1-Like Phenotype. Front Immunol. 2020 Aug 25;11:1903. PMID: 32983113; PMCID: PMC7477355. [CrossRef]
  53. Jain RK. Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer Cell. 2014 Nov 10;26(5):605-22. Epub 2014 Nov 10. PMID: 25517747; PMCID: PMC4269830. [CrossRef]
  54. Eguchi R, Wakabayashi I. HDGF enhances VEGF-dependent angiogenesis and FGF-2 is a VEGF-independent angiogenic factor in non-small cell lung cancer. Oncol Rep. 2020 Jul;44(1):14-28. Epub 2020 Apr 9. PMID: 32319650; PMCID: PMC7251661. [CrossRef]
  55. Jung WY, Min KW, Oh YH. Increased VEGF-A in solid type of lung adenocarcinoma reduces the patients’ survival. Sci Rep. 2021 Jan 14;11(1):1321. PMID: 33446784; PMCID: PMC7809025. [CrossRef]
  56. Cha JH, Chan LC, Li CW, Hsu JL, Hung MC. Mechanisms Controlling PD-L1 Expression in Cancer. Mol Cell. 2019 Nov 7;76(3):359-370. Epub 2019 Oct 24. PMID: 31668929; PMCID: PMC6981282. [CrossRef]
  57. Dammeijer F, van Gulijk M, Mulder EE, Lukkes M, Klaase L, van den Bosch T, van Nimwegen M, Lau SP, Latupeirissa K, Schetters S, van Kooyk Y, Boon L, Moyaart A, Mueller YM, Katsikis PD, Eggermont AM, Vroman H, Stadhouders R, Hendriks RW, Thüsen JV, Grünhagen DJ, Verhoef C, van Hall T, Aerts JG. The PD-1/PD-L1-Checkpoint Restrains T cell Immunity in Tumor-Draining Lymph Nodes. Cancer Cell. 2020 Nov 9;38(5):685-700.e8. Epub 2020 Oct 1. PMID: 33007259. [CrossRef]
  58. Koh YW, Lee SJ, Han JH, Haam S, Jung J, Lee HW. PD-L1 protein expression in non-small-cell lung cancer and its relationship with the hypoxia-related signaling pathways: A study based on immunohistochemistry and RNA sequencing data. Lung Cancer. 2019 Mar;129:41-47. Epub 2019 Jan 16. PMID: 30797490. [CrossRef]
  59. Chen R, Ganesan A, Okoye I, Arutyunova E, Elahi S, Lemieux MJ, Barakat K. Targeting B7-1 in immunotherapy. Med Res Rev. 2020 Mar;40(2):654-682. Epub 2019 Aug 25. PMID: 31448437. [CrossRef]
  60. Kudo M. Scientific Rationale for Combined Immunotherapy with PD-1/PD-L1 Antibodies and VEGF Inhibitors in Advanced Hepatocellular Carcinoma. Cancers (Basel). 2020; 12. [CrossRef]
  61. Tozuka, T., Yanagitani, N., Sakamoto, H., Yoshida, H., Amino, Y., Uematsu, S., Yoshizawa, T., Hasegawa, T., Ariyasu, R., Uchibori, K., Kitazono, S., Seike, M., Gemma, A., & Nishio, M. (2020). Association between continuous decrease of plasma VEGF-A levels and the efficacy of chemotherapy in combination with anti-programmed cell death 1 antibody in non-small cell lung cancer patients. Cancer Treatment and Research Communications, 25, 100249. [CrossRef]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.
Copyright: This open access article is published under a Creative Commons CC BY 4.0 license, which permit the free download, distribution, and reuse, provided that the author and preprint are cited in any reuse.
Prerpints.org logo

Preprints.org is a free preprint server supported by MDPI in Basel, Switzerland.

facebook logotwitter logolinkedin logo
MDPI Initiatives
Important Links
Subscribe

Disclaimer

Terms of Use

Privacy Policy

© 2024 MDPI (Basel, Switzerland) unless otherwise stated