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Adv Biomed Res 2023,  12:124

The effect of stem cells and vascular endothelial growth factor on cancer angiogenesis

1 Abadan University of Medical Sciences, Abadan; Department of Anatomical Sciences and Molecular Biology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
2 Department of Anatomical Sciences and Molecular Biology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran

Date of Submission02-Dec-2021
Date of Acceptance24-Apr-2022
Date of Web Publication15-May-2023

Correspondence Address:
Prof. Batool Hashemibeni
Department of Anatomical Sciences and Molecular Biology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/abr.abr_378_21

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The formation of new vessels from pre-existing vessels is known as angiogenesis. The process is controlled by stimuli and inhibitors. Angiogenesis starts as a result of the unbalance of these factors, where balance has a tendency toward the stimulus. One of the most important factors promoting angiogenesis is the vascular endothelial growth factor (VEGF). In addition to being involved in vascular regeneration in normal tissues, VEGF also takes part in tumor tissue angiogenesis. These factors affect endothelial cells (ECs) directly as well as differentiate tumor cells from endothelial cells and play an active role in tumor tissue angiogenesis. Angiogenesis partakes in the growth and proliferation of tumor tissue. Because anti-angiogenic treatment is favorable in existing cancer therapies, the potential benefits should be considered. One of these new therapies is cell therapy using mesenchymal stem cells (MSCs). Research on MSCs remains controversial because much of the earlier research on MSCs has shown their effectiveness, but more recent research has identified harmful effects of these cells. This article reviews the role of stem cells and their secretions in the angiogenesis of tumor tissues.

Keywords: Angiogenesis, cancer, mesenchymal stem cells, vascular endothelial growth factor

How to cite this article:
Moradi-Gharibvand N, Hashemibeni B. The effect of stem cells and vascular endothelial growth factor on cancer angiogenesis. Adv Biomed Res 2023;12:124

How to cite this URL:
Moradi-Gharibvand N, Hashemibeni B. The effect of stem cells and vascular endothelial growth factor on cancer angiogenesis. Adv Biomed Res [serial online] 2023 [cited 2023 Jun 7];12:124. Available from:

  Introduction Top

Angiogenesis is a highly complex process involving a range of cell types and signaling pathways. Neovascularization requires the activation and proliferation of endothelial cells (ECs). Activation of Ecs by factors such as the vascular endothelial growth factor (VEGF) gives rise to new blood vessel formation. Studies have indicated that VEGFs induce angiogenesis in vitro as well as in vivo.[1],[2],[3],[4] In addition to normal tissue, angiogenesis can also occur in tumor tissue.[5],[6],[7],[8],[9] The development of new vessels begins in pre-malignant conditions as the demand for oxygen and nutrients by the growing cancer cell mass increases.[10] The developing vessels in tumors are unlike normal vessels. In tumors, vessels are irregular in diameter, have thin walls, and are leaky.[11],[12] Cancer can be treated with surgery, chemotherapy, or radiation therapy.[13] The abnormal vascularity can make tumors resistant to chemotherapeutic agents. Anti-angiogenic therapy suppresses tumor growth.[14] One of the new methods for treating cancer is the use of stem cells.[15] Some studies have indicated that stem cells have therapeutic effects on tumor tissue, whereas others have provided evidence of the negative effects of these cells.[16] Mesenchymal stem cells (MSCs) are involved in tumorigenesis, including induction of angiogenesis,[17] stimulation of epithelial–mesenchymal transition (EMT) and tumor metastasis,[18] and inhibition of tumor cell apoptosis.[19] MSCs suppress tumor growth by inhibiting angiogenesis,[20] inducing cell cycle arrest and apoptosis[21] [Figure 1]. This article provides an overview of the role of stem cells and vascular endothelial growth factors in cancer angiogenesis.
Figure 1: Schematic image of angiogenesis switch

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  Data Acquisition Top

Scientific publications, journals, and textbooks were excluded from the search. In vivo and in vitro studies were both evaluated equally. Two independent researchers reviewed the included data, abstracts, titles, and full texts to determine their relevance for inclusion in the study. The search terms used were “cancer,” “angiogenesis,” “stem cell,” “paracrine secretions,” “vascular endothelial growth factor,” TGF-β, TGF-α, FGF2, PDGF, BFGF, granulocyte colony-stimulating factor, granulocyte colony-stimulating factor, interleukin-8 (IL-8), hepatocyte growth factor, epidermal growth factor, and other factors. No methodological search filter was applied. Scientists in related fields were contacted to assess the findings and conclusions of the related literature. In the event that additional information was needed, the authors were contacted whenever possible.

  Angiogenesis Top

New blood vessels develop through vasculogenesis, angiogenesis, arteriogenesis, and collateral growth.[17] Angiogenesis is known as the process by which new blood vessels form from pre-existing blood vessels.[5] It is a complex four-step process involving the destruction of the basement membrane, the activation of ECs, the proliferation of ECs, and the continuation of the process under the influence of angiogenic (pro-angiogenic) factors.[18] The reason for the complexity of the process is the requirement for a variety of biological interactions, including several cell types, angiogenic factors, and extracellular matrix. Typically, angiogenesis occurs in the fetal and adult stages. In adulthood, it plays a vital role in wound healing and the female reproductive cycle, such as ovulation, follicle development, corpus luteum formation, progesterone release, endometrial growth, and embryo implantation. In addition, this process plays an important role in the progression of cancer.[5],[19],[20] In 1971, Folkman was the first person to propose that tumor growth depends on the induction of angiogenesis. Subsequently, studies have shown the essential role of angiogenesis in tumor metastasis because it can provide the basis for tumor cells to metastasize farther away.[20] It also diminishes tumor access to chemotherapy drugs.[14] Many factors are involved in regulating angiogenesis, which are secreted by cells such as ECs, cancer cells, stromal cells, blood, and extracellular matrix.[5] These factors consist of pro-angiogenic factors including BFGF, VEGF,[21],[22] TGF-β, TNF-α, FGF2, PDGF, epidermal growth factor, angiogenin, angiopoietin,[23] granulocyte colony-stimulating factor, interleukin-8 (IL-8),[24] and hepatocyte growth factor.[25] Anti-angiogenic factors consist of angiostatin, thrombospondin-1 and -2, platelet factor-4, endostatin, anti-thrombin III fragment, osteopontin, collagen, kininogen domains, vasostatin, calreticulin, soluble, and the tissue inhibitors of metalloproteinases.[5] Interaction and balance between pro-angiogenic and anti-angiogenic factors regulate angiogenesis[26] [Figure 1]. When the balance between the factors is disturbed in such a way that the balance moves toward the stimulus, the ECs become active, a change in the expression of genes and proteins occurs, and eventually, angiogenesis starts. Therefore, in angiogenesis, it is not sufficient to increase pro-angiogenic factors, but also a reduction in the expression of anti-angiogenic factors is required.[20] Hypoxia stimulates angiogenesis in tumor tissue by increasing the expression of the VEGF and other angiogenic stimuli.[5] The VEGF plays a major role in pathological angiogenesis, such as macular degeneration, diabetic retinopathy, inflammatory processes, tumor growth, and metastasis.[27]

  Effect of the Vegf on Cancer Cells Top

The role of the VEGF in tumor angiogenesis was established via stimulation of VEGFRs on the tumor endothelium. However, there is increasing evidence that the VEGF may have an additional role in cancer via the stimulation of VEGFRs in tumor cells.[28] Several studies have demonstrated the presence of VEGFRs in cancer cells, such as breast cancer, pancreatic, prostate, and lung cancer cells.[29],[30],[31],[32] Therefore, the expression of VEGFRs by tumor cells involves the major role of VEGF/VEGFR signaling in these tumors. Yanga et al. (2015) demonstrated that VEGF-B is a vascular remodeling factor promoting cancer metastasis and that targeting VEGF-B may be an important therapeutic approach for cancer metastasis[33] Positive regulation of the VEGF/neuropilin-1 axis in breast cancer tumorigenesis and metastasis may be associated with enhanced EMT and NF-B and catenin signaling.[34] Zhao et al. (2015) showed that VEGF promotes tumor-initiating cells' (primary breast and lung cancers) self-renewal through VEGFR-2/STAT3 signaling[35] Myeloid-derived suppressor cells (MDSCs) induced through VEGF signaling play important roles in tumor immune evasion in ovarian cancer, and the targeting of VEGF-induced MDSCs represents a promising treatment for ovarian cancer.[36] Kong et al. (2020) showed that VEGF-C mediates tumor growth and metastasis by promoting EMT-epithelial breast cancer cells.[37] Tomida et al. (2018) indicated that VEGF/VEGF-R inhibitors directly act on colon cancer cells and activate their evasive adaptation via various mechanisms.[38]

  Effect of Mscs on Cancer Cells Top

One of the important steps in angiogenesis is the differentiation of progenitor ECs into ECs and the proliferation of the resulting cells. Several different signaling control this process.[5] The tumor microenvironment consists of different types of cells that affect tumor angiogenesis.[28] A lack of balance between angiogenic factors results in the pathogenesis of many diseases. For example, insufficient angiogenesis causes ischemic disease, and high levels of it can lead to cancer.[29] Small vessels only contain ECs, but larger vessels contain mural cells (pericyte and vascular smooth muscle).[17] Nowadays, angiogenic therapy is just as important as surgical treatments, chemotherapy, and radiation therapy. Cancer anti-angiogenesis treatments have an advantage over chemotherapy. They do not cause toxicity and have a synergistic effect in the use of other treatments such as chemotherapy, radiation therapy, and gene therapy.[20] Therefore, the advantage of anti-angiogenesis therapy resulted in promoting researchers to come up with new anti-angiogenesis treatments for cancer. One of the new methods in the treatment of cancer is the use of MSCs.[15]

One of the cells used to treat breast cancer is the stem cell.[30] Stem cells are a group of undifferentiated cells that can discriminate into different types of specialized cells.[31] MSCs are a population of stem cells with self-renewal and multipotentiality that hold great promise for regenerative medicine.[32] MSCs move to tumor sites and then incorporate between the tumor stroma.[34],[39] These cells interact with cancer cells.[40],[36] MSCs have been isolated from bone marrow, adipose tissue, and umbilical cord blood. MSCs promote tumor growth and suggest that the crosstalk between tumor cells and MSCs increased the expression of pro-angiogenic factors, which may have induced tumor cell proliferation and angiogenesis thereby increasing solid tumor growth.[41] Adipose tissue-derived stem cells (ADSCs) significantly promoted the proliferation and invasion of ovarian cancer cell (EOC) in both direct and indirect co-culture assays. In addition, after co-culture with ADSCs, EOC cells secreted higher levels of matrix metalloproteinases (MMPs), and inhibition of MMP2 and MMP9 partially relieved the tumor-promoting effects of ADSCs in vitro. Omental ADSCs play a promotive role during ovarian cancer progression.[42] IL-8 secreted by MSCs promotes colorectal cancer angiogenesis and growth and can therefore serve as a potential novel therapeutic target.[43] MSCs promote the progression of colorectal cancer via AMPK/mTOR-mediated NF-κB activation.[44] CXCL1/8 secreted by hADSCs could promote breast cancer angiogenesis and therefore provide better understanding of safety concerns regarding the clinical application of hADSCs and suggestions for further novel therapeutic options.[45] Human adipose-derived mesenchymal stromal cells may promote progression and metastatic spread in breast cancer through a switch to a more malignant phenotype with worse prognosis.[46]

  MSCs and Their Differentiation into ECs Top

To create a vascular network, it is necessary to have a source of ECs, which are usually taken from blood vessels and umbilical cords. Because it is difficult to access these resources, the production of these cells is very limited. Therefore, searching for a better source to obtain these cells is essential. Stem cells are often used to differentiate into EC. Angiogenic factors are frequently used to differentiate MSCs from ECs.[47] MSCs can have quasi-endothelial properties in pro-angiogenic environments,[48] allowing them to participate in the processes of proliferation, migration, endothelial tube formation, and ultimately angiogenesis.[49] Expression of endothelial markers shows MSC differentiation into ECs.[47] In vitro and in vivo studies have shown that MSCs that invade ECs are able to form blood vessels.[47],[49] MSCs could potentiate angiogenesis due to their ability to migrate and create capillary-like structures, and this is achieved through growth factors.[50] MSCs present in cancerous tissue stroma play a key role in the proliferation of cancer cells, metastases, and resistance to chemotherapy.[51] MSCs are found in many tissues such as the umbilical cord, peripheral blood, skeletal muscle, adipose tissue,[52] dermis,[53] and synovial membrane.[54] MSCs are positive for CD105, CD73, and CD90, and negative for CD45, CD34, CD14, or CD11b, CD79, or CD19, and HLA-DR molecules.[55],[56] The umbilical cord MSCs do not express MHC types 1 and 2, so they are good candidates for clinical use.[57] Studies have shown that MSCs stimulate the growth and metastasis of tumors, whereas other studies have reported that MSCs suppress tumor growth and metastasis.[16],[39] However, in connection with the role of tumor suppression, MSCs can suppress tumor growth through the AKT signaling pathway.[58] MSCs can also prevent cancer of human liver cancer cells and breast cancer cells by inhibiting the Wnt signaling pathway.[46],[59] In addition, MSC inhibits tumor growth through anti-angiogenic activity,[60] low expression of the X-dependent apoptotic protein inhibitor (XIAP),[61] PI3K signaling pathway molecules,[58] and inhibition of cell cycle progression.[62] MSCs secrete angiopoietin 2, VEGF, IL8, BFGF,[63] PDGF,[64] and IL6.[65] Uterine endometrial stem cells secrete angiogenic factors such as MMP3, MMP10, GM CSF, angiopoietin 2, and PDGF-BB.[66] Stem cells derived from fat, uterine endometrium, and placenta secrete angiogenic factors including VEGF, HGF, BFGF, TGFB, IGF1, PDGF, MMP3, and MMP10.[64],[67] MSCs isolated from different tissues, depending on their origin, may have different potentials for clinical applications and there are differences in regression.[64] ADSCs secrete more angiogenic agents and are more capable of forming new blood vessels than endometrial and umbilical cord-derived stem cells.[68] Likewise, fat-derived MSCs have more vascular potential than bone-derived MSCs and umbilical cords.[69],[70] ADSCs promote the development of breast cancer by releasing cytokines such as CXCL1 and CXCL8.[43],[47],[48],[49],[50],[51],[52],[53],[54],[55],[56],[57],[58],[59],[60],[61],[62],[63],[64],[65],[66],[67],[68],[70],[71],[72] MSCs with IL6 secretion increase endothelin 1 in the tumor, thereby stimulating ECs and causing angiogenesis.[65] ADSCs secrete angiogenic factors such as HGF.[64] ADSC are affected by containing FGF2 receptors and are differentiated into ECs.[73] A 2017 study found that direct cell-to-cell contact between stem cells and ECs caused stem cells to differentiate into ECs.[74] TGF-β also differentiates stem cells into ECs and lymph vessels.[75] In addition to growth factors, the suitability and effectiveness of the culture medium is a complementary approach to cell growth because it can have a major impact on cellular behavior and cell differentiation.[47] The most common ship environment used for ECs is EGM2. When bone marrow-derived stem cells are cultured in the medium containing EGM2, the expression of endothelial markers such as CD31, VWF, and VEGFR2 increases.[76] Factors such as KDR, CD34, CD31, FLT1, V-cadherin, and VCAM1 are some of the signs that differentiate ECs from stem cells.[77] SOD1 is a factor secreted by MSCs through paracrine pathways that improves the damage and dysfunction of ECs due to lung cancer chemotherapy.[78] FGF is a growth factor involved in angiogenesis, wound healing, embryonic development, and a number of other endocrine signaling pathways. Cultivated ADSCs in the culture medium containing FGF showed that ADSCs were differentiated into ECs, and markers represent ECs.[79] FGF has a multiplier effect on MSCs and, most prominently, controls ADSC differentiation and plays a role in the migration of ECs.[79] Zhang et al. have found that an EGM2 culture medium containing VEGF increased the levels of the mRNA VEGF and eNos in ADSCs. The BFGF also stimulates ECs.[71],[62],[63],[69],[70],[71],[72],[73],[74],[75],[76],[77],[78],[80]

  VEGF: A Key Factor in Cancer Angiogenesis and MSC Differentiation into ECs Top

The VEGF is a major factor in angiogenesis, stimulating the growth of new blood vessels from previous vessels and providing access to oxygen and nutrients for tumors.[81] The VEGF is an important pro-angiogenic factor in breast cancer and is involved in the growth, survival, and invasion of tumor cells through autocrine pathways.[82] Studies have shown that the suppression of tumor suppressor genes such as P53 and the activation of oncogenic genes such as Kras, Hras, v-Src, human epidermal growth factor HER 2, HER1/EGFR, FOS, trkB, V-p3K, PTTG1, and Bcl2 increase VEGF expression in tumor cells.[83] Family members of the VEGF include five glycoproteins (VEGF-A, VEGF-B, VEGF-C, VEGF-D, and VEGF-E) and placenta growth factors 1, 2, and 3. VEGF-A is the most important member of the VEGF family, which mainly targets ECs.[82] PDGF and HIF-1α induce VEGF expression in the tumor cells.[84] The VEGF is then attached to its receptor on the surface of ECs, causing the cells to grow and proliferate. However, it increases MMP expression in tumor cells.[82] There is also a VEGF receptor on tumor cells.[85] This growth factor is involved in the migration, proliferation, and differentiation of MSCs into ECs.[86] The study by Sami G in 2017 showed that the VEGF is involved in the differentiation of MSCs into ECs.[87] The study by SG Ball et al. revealed that the VEGF stimulates the proliferation and migration of MSCs by activating the PDGF (5).[88] One of the signaling pathways through which the VEGF can play a role in distinguishing MSCs from ECs is MAPK, which is an intracellular pathway.[89] ERK1/2-c-jun NH2 and P38 are members of the cascade MAPK.[90] When VEGFR2 is activated, PLC-γ phosphorylates and activates the MAPK signaling pathway.[87] In 2008, J Xu demonstrated that VEGF mediates the differentiation of bone-derived MSCs into ECs by activating the MAPK pathway.[91] VEGF is the most common growth factor for distinguishing bone marrow MSCs from ECs. The NFKB pathway regulates VEGF secretion from MSCs. Inhibition of this pathway reduces its secretion.[6] The VEGF, along with FGF, induces c-Kit, IL-3R, M-CSF, CSFR1, Flt3L, Flt3, and CXCR4 receptors in ECs, resulting in an increased ability of the VEGF and FGF to form vascular tubes. STAT3 and P38 MAPK pathways cause VEGF secretion from MSCs.[7] The Rho family plays an important role in the migration and angiogenesis of VEGF-induced ECs. The VEGF activates the Rho/ROCK messaging pathway and stimulates nuclear translocation of myocardin-related transcription factor-A (MRTE-A) and differentiates MSCs into ECs.[7] Therefore, VEGF production by MSCs may be a crucial factor responsible for the angiogenic potential of MSCs and can promote angiogenesis in cancer.[79],[80],[81],[82],[83],[84],[85],[86],[87],[88],[89],[90],[91]

  Conclusions Top

Whereas the potential of MSCs to induce angiogenesis leading to tissue regeneration has been well documented in preclinical and clinical studies, the effect of paracrine factors secreted by these MSCs is currently under investigation. Considering cancer as a common cause of death worldwide, the use of stem cells to treat the disease requires serious contemplations and observations. Therefore, more studies should be done in relation to the secretory factors of stem cells and the mechanism of action of these factors.

Abbreviations are used: VEGF: vascular endothelial growth factor, ECs: endothelial cells, MSCs: mesenchymal stem cells, TGF-β: transforming growth factor-beta, TGF-α: transforming growth factor-alpha, FGF2: fibroblast growth factor 2, PDGF: platelet-derived growth factor, BFGF: basic fibroblast growth factor, TNF-α: tumor necrosis factor α, TIMPs: tissue inhibitors of metalloproteinases, CD: cluster differentiation, MHC: major histocompatibility complex, HLA-DR: human leukocyte antigen—DR isotype, XIAP: X-dependent apoptotic protein inhibitor, PI3 K: phosphatidylinositol-3-kinase, MMP3: matrix metalloproteinases, GM CSF: granulocyte–macrophage colony-stimulating factor, PDGF-BB: platelet-derived growth factor-BB, HGF: hepatocyte growth factor, IGF1: insulin-like growth factor, CXCL: chemokine (C-X-C motif) ligand, ADSC: adipose tissue-derived stem cells, EGM: endothelial growth medium, vWF: von Willebrand factor, VCAM: vascular cell adhesion molecule, SOD1: superoxide dismutase, EGM2: endothelial cell growth medium 2, MAPK: mitogen-activated protein kinase, ERK1: extracellular signal-regulated kinase.

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