VEGF-Leptin Crosstalk in Breast and Ovarian Cancer: Drivers of Angiogenesis and Progression

Abstract

Breast and ovarian cancers (BC and OC) remain among the leading causes of cancer-related deaths among women worldwide. Their progression is critically dependent on tumor angiogenesis and a permissive metabolic microenvironment. Vascular endothelial growth factor (VEGF) is a key factor in tumor angiogenesis and neovascularization. Leptin, conversely, a hormone that is produced by adipocytes, serves as an important mediator of tumor proliferation, inflammation, and metastasis. Increasing evidence suggests that VEGF and leptin act via multiple overlapping oncogenic pathways. They collectively promote tumor growth, survival, and angiogenesis. Obesity, hypoxia, and interactions between adipose tissue and the stroma further enhance this oncogenic axis by increasing the expression of VEGF and leptin and supporting metabolic reprogramming of the tumor. In BC and OC, persistent activation of the VEGF-leptin network contributes to aggressive disease progression, treatment resistance, and unfavorable clinical outcomes. Studies have indicated cytokine release, hypoxia and necrosis induction, angiogenesis, and tumor metastasis by interconnected immune pathways mediated by leptin and VEGF. Important roles of different receptors have also been uncovered in several in-vitro and in-vivo experiments. The findings have opened avenues for developing targeted monotherapies and combination therapeutic strategies to control tumor progression by inhibiting diverse signaling pathways. This review highlights the reciprocal VEGF–leptin feedback interaction in obesity-associated BC and OC, integrating evidence form biomarker studies and therapeutic perspectives. It also examines the influence of obesity and hypoxia on tumor progression and discusses current therapeutic strategies targeting this interconnected angiogenic-metabolic interaction.

Introduction

Global Epidemiology and Clinical Burden

Breast cancer (BC) and ovarian cancer (OC) remain among the most significant cancers, contributing significantly to global cancer incidence and mortality.¹ BC is a frequently diagnosed cancer that accounts for about 11.6% of all cancers globally and approximately one-quarter of all newly diagnosed cancers among women.^2,3 Contrarily, OC is much more complex and is usually diagnosed at a late stage. Both are highly heterogeneous diseases and are caused by a variety of factors such as age, gender, lifestyle, family history, hormonal dysregulation, environmental conditions, and genetic predispositions.^1,4 According to GLOBOCAN 2022 estimates, there were approximately 2.3 million new cases of BC and 0.66 million BC-related deaths worldwide. The latest IARC analysis estimates approximately 3.2 million cases annually by 2050, representing a 38% increase from 2022 mainly in low- and middle-income countries.³ The five-year survival rate is almost 90% in high-income countries, but is significantly lower in resource-limited regions due to insufficient access to early detection and comprehensive treatment.⁵

OC contributes disproportionately to mortality among gynecological cancers. Worldwide, an estimated 324,398 new cases of OC and 206,839 deaths were reported in 2022. Due to a lack of reliable screening methods and nonspecific clinical symptoms, the disease is often diagnosed at advanced stages, resulting in a poor prognosis and five-year survival rates of 30% to 50% in most countries.⁶ Metastasis plays an important role in promoting ovarian tumor progression, reducing patient survival rates. While the global age-standardized mortality rate for OC decreased slightly from 4.73 to 4.06 per 100,000 inhabitants between 1999 and 2021, mortality remains alarmingly high, and incidence rates continue to rise in several regions of Asia and Africa.^7,8 The generally accepted mechanism of dissemination of OC involves a transcoelomic route in which OC cells shed from the primary tumor site and enter the peritoneal cavity. The cells are then carried by the physiological movement of peritoneal and ascitic fluid and attach to mesothelial surfaces, subsequently invading the peritoneum and omentum. Due to a lack of research and limitations in early diagnosis and restricted access to targeted therapies, significant disparities in treatment outcomes persist.⁸

Cancer progression and manifestation are highly complex, depending on the molecular and physiological changes in the tumor cells. The genetic and environmental differences cause variations in the tumor microenvironment (TME).⁵ One of the important hallmarks of cancer progression is the induction of angiogenesis, which introduces visible differences in the tumor and normal cells’ blood vasculatures.⁹ It causes the progression and dissemination of tumor cells by neovascularization, caused by pro- and anti-angiogenic factors such as fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), interleukin, transforming growth factor-β (TGF- β), and platelet-derived growth factor (PDGF).^10,11 In normal cells, the blood vessel plexus represents cohesive structures that evenly distribute nutrients and oxygen to all the cells. However, angiogenesis causes the sprouting of new blood vessels from the existing ones by solid tumors.¹² This facilitates the growth and metastatic spread of the cancer cells by transporting the required nutrients, oxygen, and immune cells to the TME.¹³

Beyond angiogenic drivers, metabolic factors like leptin further shape the tumor microenvironment. Obesity-related metabolic dysfunction is increasingly recognized as a key factor in the progression of BC and OC.¹⁴ Leptin, a hormone that is chronically elevated in obese individuals, has been shown to play a crucial role in cancer biology. It is produced by adipocytes and is primarily involved in regulating energy homeostasis.¹⁵ It exerts tumor-promoting effects by enhancing cell proliferation, inflammation, and angiogenesis, particularly in obesity-associated cancers.¹⁶ Leptin is found to activate oncogenic signaling pathways, including JAK/STAT3, PI3K/Akt, and VEGF-mediated pathways. Recent research suggests that the interaction between the leptin and VEGF pathways contributes to the development of a tumor-friendly microenvironment.¹⁷ The functional interaction between VEGF and leptin signaling pathways forms a regulatory axis that enhances angiogenic and proliferative responses in BC and OC.¹⁸ This signaling axis represents a crucial link between metabolic dysregulation and tumor angiogenesis, potentially providing new insights into disease progression and therapeutic approaches.¹⁹

BC and OC have distinct tissue origins, however, both are female reproductive malignancies that may be influenced by hormonal, metabolic, inflammatory, and angiogenic signaling. In both cancers, adipokine-mediated signaling and VEGF-driven angiogenesis contribute to tumor growth and progression. Leptin, through its receptor and downstream pathways, interacts with angiogenic signaling and influences VEGF-mediated responses. It is considered not only a regulator of energy homeostasis but also a multifunctional adipokine with important effects on cancer biology. Unlike prior reviews, this manuscript emphasizes the reciprocal VEGF-leptin feedback interaction in obesity-associated BC and OC, integrating biomarker and therapeutic perspectives. It aims to explore the molecular interactions between the VEGF and leptin signaling pathways in BC and OC, particularly regarding their roles in angiogenesis and tumor proliferation (Figure 1). Understanding these interactions can contribute to the identification of new biomarkers and support the development of targeted therapies.

Figure 1.

Genetic predispositions, environmental, immunologic, and metabolic factors play a role in the growth and proliferation of tumor cells and adipocytes. Adipocytes secrete leptin, and tumor cells secrete VEGF; conversely secrete cytokines and chemokines. These activate signaling processes and cause the growth, proliferation, and metastasis of tumor cells by inducing hypoxia, neovascularization, and immune signaling.

Literature Search and Review Methodology

A structured literature search was conducted to identify and synthesize published evidence to determine the role of the VEGF-leptin signaling axis in BC and OC. The search is focused on their involvement in tumor angiogenesis, cancer-cell proliferation, survival, invasion, metastasis, diagnosis, prognosis, and therapeutic targeting. The literature was searched for the preceding 20-years (2006–2026) between January and May 2026 using PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar. Search terms included combinations of “VEGF”, “vascular endothelial growth factor”, “VEGF signaling”, “leptin”, “leptin signaling”, “leptin receptor”, “angiogenesis”, “tumor proliferation”, “breast cancer”, “breast carcinoma”, “ovarian cancer”, and “ovarian carcinoma”. Boolean operators (AND/OR) were used to combine the search concepts, with search terms adapted according to the requirements of individual databases.

Eligibility Criteria and Study Selection

Studies were considered eligible if they investigated BC and OC in the context of VEGF and/or leptin signaling. Particular emphasis was placed on studies investigating VEGF- and leptin-mediated signaling pathways; angiogenesis; tumor-cell proliferation, survival, migration, invasion, and metastasis; clinicopathological associations; and diagnostic or prognostic applications. Both preclinical and clinical evidence, including cellular and molecular studies, observational research, clinical trials, and studies evaluating established, emerging, or investigational therapeutic approaches, were considered. The studies that did not provide relevant information on VEGF or leptin signaling in the context of BC and OC, or that fell outside the scope of this review, were excluded. Studies focused exclusively on other cancer types were also excluded.

Study selection was performed by initially screening the titles and abstracts of retrieved publications. Duplicate records were removed before the final selection of relevant literature. This was followed by assessment of the full texts of potentially relevant articles. The selected literature was subsequently organized thematically according to the major objectives of the review. EndNote reference-management software was used for organization and management of retrieved literature, removal of duplicate records, and management of citations and references throughout manuscript preparation.

VEGF Signaling in Cancer

VEGF is highly expressed in tumor cells. It stimulates the process of angiogenesis and facilitates the intravasation and dissemination of tumor cells.²⁰ In BC and OC, increased VEGF expression is strongly associated with enhanced tumor aggressiveness, increased metastatic potential, and a poor prognosis. Hypoxic conditions in the TME further enhance VEGF production by activating hypoxia-inducible factor 1α (HIF-1α). The signaling pathway encompasses the involvement of various types of VEGF glycoproteins, receptors, and ligands.²¹ All of these collectively activate and promote the signaling axis, stimulating neovascularization.²² The VEGF family comprises several structurally related glycoproteins, including VEGF-A, VEGF-B, VEGF-C, VEGF-D, and placental growth factor (PlGF), which collectively regulate angiogenesis and lymphangiogenesis.²³

VEGF-A is the most studied signaling protein and is considered as a principal mediator of tumor-associated angiogenesis. VEGF ligands exert their biological functions by binding to three important receptor tyrosine kinases: VEGFR-1 (Flt-1), VEGFR-2 (KDR/Flk-1), and VEGFR-3 (Flt-4), which are primarily expressed in endothelial cells.²⁴ VEGF-A binds predominantly to VEGFR-2 and initiates strong pro-angiogenic signaling, promoting endothelial cell proliferation and migration as well as vascular permeability.²⁵ In contrast, VEGF-B and PlGF preferentially interact with VEGFR-1 and are involved in vascular remodeling and inflammation regulation.²⁶ VEGF-C and VEGF-D primarily activate VEGFR-3 and play a crucial role in lymphangiogenesis and lymphatic metastasis, particularly in aggressive malignancies including BC and OC.²⁷

The binding of VEGF ligands to their cognate receptors induces receptor dimerization and subsequent auto-phosphorylation. This triggers several downstream signaling pathways, such as PI3K/Akt and MAPK/ERK, which are essential for vascular development and tumor growth.²⁸ The PI3K/Akt pathway promotes endothelial cell survival, nitric oxide synthesis, and resistance to apoptosis, while the MAPK/ERK pathway primarily regulates cell proliferation and migration.^29,30 VEGF signaling also activates the phospholipase C-gamma (PLCγ)/protein kinase C (PKC) signaling pathway, which contributes to endothelial cell differentiation and increased vascular permeability.³⁰ Through the coordinated activation of these pathways, VEGF regulates angiogenic sprouting, vascular remodeling, and the formation of the aberrant vascular structure, which are characteristic features of the TME.³¹

Leptin Signaling in Cancer

Leptin is a 16 kDa polypeptide cytokine consisting of 167 amino acids. It is encoded by the LEP gene present on chromosome 7q31.3 in humans. It belongs to the superfamily of long-chain helical cytokines, which also includes interleukin-6 (IL-6) and oncostatin M.³² It is predominantly secreted by white adipocytes in proportion to fat mass and serves as a hormonal signal for adequate energy supply. It acts on hypothalamic neural circuits to suppress appetite and increase energy expenditure.³³ Blood leptin concentration correlates strongly with body fat percentage. Obese individuals exhibit chronically elevated leptin levels, often 10–50 ng/mL, compared with 3–15 ng/mL in lean adults.³⁴ These increased levels are associated with central leptin resistance and alterations in neuroendocrine function.³⁵

Leptin has diverse pleiotropic effects in the immune system, hematopoiesis, bone metabolism, and reproduction. The biological effects of leptin are mediated by the leptin receptor (Ob-R), a member of the class I cytokine receptor family encoded by the LEPR gene. Due to alternative splicing, several isoforms of Ob-R exist.³⁶ These are expressed in the hypothalamus, endothelial cells, immune cells, and numerous cancer cell types, including breast and ovarian tumor cells.³⁵ The long isoform Ob-Rb is considered the primary signaling receptor in which conformational changes occur upon binding of leptin molecules. This is followed by the activation of associated intracellular kinases and downstream oncogenic signaling pathways. Increased expression of leptin receptors has been observed in aggressive tumors and is frequently associated with a poor prognosis and increased tumor invasiveness.^37,38

Leptin is increasingly recognized as an important tumor-promoting adipokine that links obesity to cancer progression. The structural homology of leptin to cytokines and its ability to activate overlapping cytokine receptor signaling pathways position it as a functionally important pro-inflammatory and pro-proliferative mediator in the TME.³⁹ The expression of diverse molecules responsible for the proliferation, differentiation, inflammation, and angiogenesis, such as cyclin D1, CDK2, c-Myc, BCL2, leukemia inhibitory factor (LIF), LIF receptor (LIFR), β3 integrin, IL-1, IL-1R, and IL-1Ra, increases during leptin signaling.⁴⁰ This promotes chronic inflammation, angiogenesis, epithelial-mesenchymal transition (EMT), cancer stem cell maintenance, and metastasis. It can activate the JAK/STAT3 and MAPK/ERK pathways, which promote the transcription of genes involved in cell cycle progression, inflammation, and anti-apoptotic pathways.⁴¹ It can also stimulates the PI3K/Akt pathway, thereby enhancing tumor cell survival, metabolic adaptation, and chemotherapy resistance.⁴²

VEGF and Leptin Signaling in Tumor Microenvironment

Leptin-Induced Regulation of VEGF Expression

A characteristic feature of the leptin-VEGF axis is the ability of leptin to act as an inducer of VEGF transcription. VEGF and leptin bind to structurally distinct receptors, but their downstream signaling networks converge at common intracellular junctions and control proliferation, survival, and angiogenesis (Table 1).⁴³ This signaling convergence may contribute to the oncogenic synergy observed in BC and OC. Recent integrative analyses confirm that obesity-associated hyperleptinemia in BC increases VEGF expression and enhance tumor angiogenesis via both canonical (JAK2/STAT3) and non-canonical (NF-κB and HIF-1α) pathways.^44–46 These pathways are activated by both VEGF and leptin, but their relative contributions differ depending on tumor cell type and are influenced by receptor isoform, TME signaling, and interaction with steroid hormone receptors.¹⁹

Table 1.

Convergent Intracellular Signaling Pathways Downstream of VEGF and Leptin in Breast and Ovarian Cancer

Pathway	Key Role Downstream of VEGF	Key Role Downstream of Leptin	Convergent Oncogenic Output	Ref.
PI3K/Akt pathway	Endothelial cell survival, vascular permeability, and eNOS-mediated vasodilation	Tumor cell survival, proliferation, and anti-apoptotic Bcl-2 induction	Resistance to apoptosis; sustained pro-survival phenotype	[44,45]
MAPK/ERK pathway	Endothelial proliferation and migration via PLCγ–PKC–RAF cascade	Cell-cycle progression via cyclin D1 and c-Myc upregulation	Sustained proliferation and angiogenic sprouting	[45,46]
JAK2/STAT3 pathway	Endothelial inflammatory signalling and survival gene expression	Transcriptional activation of VEGFA, BCL2, and MMP-9	Direct STAT3-mediated VEGF induction; angiogenic switch activation	[47,48]
mTOR signaling pathway	Endothelial protein synthesis and vessel maturation	Cap-dependent translation of HIF-1α, cyclin D1, VEGF	Amplified translation of pro-angiogenic and proliferative proteins	[49]
Hypoxia-inducible factor 1-alpha/NF-κB	Hypoxia-induced VEGF transcription; immune modulation	Leptin-induced HIF-1α stabilization and NF-κB activation	Hypoxia–adipokine crosstalk; coordinated VEGF upregulation	[44]

Abbreviations: PI3K, phosphoinositide 3-kinase; ERK, extracellular signal-regulated kinase; STAT3, signal transducer and activator of transcription 3; mTOR, mammalian target of rapamycin; HIF-1α, hypoxia-inducible factor-1α; NF-κB, nuclear factor κB.

Leptin contributes to tumor cell proliferation, invasion, and resistance to apoptosis by promoting VEGF expression and activating angiogenic signaling and downstream signaling pathways, such as JAK2/STAT3, PI3K/Akt, and MAPK/ERK. This is achieved through the integration of cytokine, hormone, and metabolic signals into a coordinated angiogenic and survival-promoting effect.^47,48 The HIF-1α and NF-κB axis act as the transcriptional mediators of leptin-induced VEGF expression. Leptin enhances the VEGF transcription by promoting NF-κB activation through JNK and p38 MAPK pathways and activates HIF-1α through PI3K and MAPK-dependent signaling.⁴⁴ STAT3 binds to the regulatory regions of VEGFA gene and interacts with HIF-1α at hypoxia-responsive elements (HREs) to promote VEGFA transcription and angiogenesis.⁴⁶ NF-κB amplifies the response under the inflammatory conditions characteristic of adipose tissue. HIF-1α accumulation is further promoted by leptin under normoxic conditions, which promotes VEGF induction in the absence of overt hypoxia. Consequently, by promoting VEGF expression in obesity-associated TME, leptin signaling can assist in tumor angiogenesis and vascular remodeling.⁴² Leptin signaling can also contribute to tumor growth and endocrine signaling by interacting with estrogen receptor pathways, specifically in ER-positive BC.^43,50

VEGF Feedback Effects on Leptin Signaling

Endothelial-Tumor Cell Communication

In TME, bidirectional communication between endothelial and tumor cells plays an important role in coordinating angiogenic and metabolic pathways. Tumor cells secrete VEGF, which stimulates endothelial cell proliferation, migration, and vascular remodeling.⁵¹ Activated endothelial cells release cytokines, growth factors, and inflammatory mediators that further promote tumor growth. VEGF-induced endothelial activation increases local hypoxia, vascular permeability, and inflammatory signaling.⁵² These effects may contribute to increased leptin production and Ob-R expression in tumor tissue, however there is limited evidence for VEGF-mediated regulation of leptin. In contrast, experimental studies in BC models support leptin-induced VEGF expression and leptin-mediated activation of endothelial VEGFR2.⁴⁴ A possible reciprocal feedback interaction between VEGF and leptin signaling is supported by these findings as VEGF can affect leptin secretion in particular breast cancer–adipocyte models. However, direct evidence for VEGF-mediated regulation of leptin is still limited and context-dependent.⁵³ Such cross-talk between angiogenic and adipokine signaling pathways can promotes tumor cell survival, invasion, and resistance to apoptosis while simultaneously maintaining chronic inflammation in the TME. VEGF-stimulated endothelial-derived factors can additionally activate downstream oncogenic pathways in neighboring tumor cells, including the MAPK/ERK and STAT3 cascades. This may further sensitizes cancer cells to leptin-mediated proliferative signals.⁵⁴

Angiogenesis-Mediated Metabolic Signaling

The VEGF and leptin signaling pathways integrate angiogenic, inflammatory, and metabolic responses that together promote tumor growth and metastasis. In obesity-associated tumors, angiogenesis is closely linked to dysregulation of adipokines, primarily due to increased leptin signaling.⁵⁵ The VEGF-induced vascular remodeling may improves the nutrient supply to tumor tissue and facilitates adaptation to hypoxic stress by enhancing leptin-mediated anabolic and proliferative signaling.⁵⁶ Leptin and VEGF cooperatively regulate glucose uptake, lipid metabolism, and mitochondrial function through the joint activation of the PI3K/Akt/mTOR signaling axis.⁵⁷ Together, these effects can promote metabolic reprogramming and tumor growth (Figure 2). Simultaneously, hypoxia in poorly organized tumor vessels can activate HIF-1α, further increasing the expression of both VEGF and leptin. This leads to the overlapping mechanisms that link angiogenic and adipokine signaling.⁵⁸ This contributes to enhance the metabolically adaptive and pro-angiogenic microenvironment, providing maintenance of cancer stem cells and treatment resistance in BC and OC.⁵⁷ Hence, targeted inhibition of the VEGF-leptin feedback network could represent a potential strategy for interrupting obesity-related tumor progression.⁵⁸

Figure 2.

(a) In an obese woman diagnosed with breast cancer, the tumor cells grow around adipocytes, both playing a role in VEGF secretion and enhanced VEGF signaling. (b) Diverse immune cells are recruited to the tumor microenvironment, which increases the secretion of pro-inflammatory cytokines. (c) Within adipocytes, anaerobic respiration takes place, which leads to the induction of hypoxia. All these processes increase the immune signaling pathways, which causes the integration of angiogenic, inflammatory, and metabolic responses that together play a role in tumor growth and metastasis. Blue upward arrows indicate increased levels or production of the indicated factors; the blue downward arrow indicates increased conversion of pyruvate to lactate; and the red downward arrow indicates progression toward hypoxia associated with altered mitochondrial metabolism.

The VEGF-Leptin Axis in Breast and Ovarian Cancer

Obesity is increasingly recognized as a major factor in the development and progression of cancer, particularly BC and OC. Excess adipose tissue not only serves to provide energy reserves but also acts as an active endocrine organ. They secrete adipokines, pro-inflammatory cytokines, growth factors, and metabolic mediators that can alter the TME.⁵⁹ Leptin, primarily produced by white adipose tissue, has been recognized as an important adipokine, having strong tumor-promoting properties. Its circulating concentration generally increases proportionally to body fat percentage and is significantly elevated in obese individuals.⁶⁰ Although the physiological role of leptin is to regulate appetite and energy homeostasis; however, dysregulated leptin signaling contributes to tumor cell proliferation, angiogenesis, migration, and apoptosis resistance by activating various signaling pathways.⁶¹

In BC and OC, overexpression of leptin and its receptor (Ob-R) has been associated with aggressive tumor phenotype, increased metastatic potential, and poor prognosis. Hypertrophied adipocytes, chronic low-grade inflammation, hypoxia, necrosis, and impaired lipid metabolism collectively promote tumor growth and survival.⁶² Obesity-associated hypoxia can induce HIF-dependent expression of VEGF, glycolytic enzymes, and inflammatory mediators, facilitating angiogenesis, metabolic reprogramming, and adaptation to cellular stress within the TME.⁶³ Adipose-derived cytokines and metabolic substrates continuously supply cancer cells with energy and biosynthetic precursors necessary for rapid proliferation. These interconnected actions can facilitate the development of a new vascular network and the progression of metastasis. To escape the hypoxic environment, the tumor cells enter the bloodstream and metastasize to new tissue sites.^64,65

The VEGF-leptin axis may contribute to metastasis through several complementary mechanisms. (i) VEGF-C/-D-VEGFR3 signaling promotes lymphangiogenesis and lymphogenous metastasis. This is particularly relevant for axillary spread of BC and peritoneal seeding in OC.^66,67 (ii) Leptin-induced EMT and increased activity of matrix metalloproteinase-9 (MMP-9) can enhance tumor cell invasion across the basement membrane and stromal barriers. (iii) Leptin-mediated activation of STAT3 and other stemness-associated pathways maintain tumor-initiating cell populations capable of establishing secondary tumors in distant tissues.^68,69 In ER-negative BC, leptin signaling may also promote the survival of disseminated tumor cells in fat-rich metastatic niches such as bone marrow and omentum, thus contributing to disease recurrence. The findings from adipo-oncology suggest that adipocyte-derived factors can contribute to the establishment of metastatic tumor cells and associate the adipose–tumor interactions with the broader metastatic cascade.^70,71

Leptin, an upstream regulator of VEGF/VEGFR2, induces their upregulation along with independent transactivation of VEGFR2. This pro-angiogenic activity is mediated by the release of angiogenic factors, which increase the proliferation, activation, differentiation, and migration of different endothelial cells.⁶⁵ These processes are regulated by the paracrine actions of leptin that affect the stromal cells and tumor-associated macrophages. This causes the recruitment of inflammatory cells at the site of neovascularization in the TME. The tumor-associated macrophages, in turn, produce potent pro-angiogenic factors such as TNF-α, VEGF, FGF-2, IL-1β, IL-6, IL-8, and Notch-associated signaling factors.^72,73 The impact of leptin-induced upregulation of VEGF/VEGFR2 mRNA and protein expression was explored in 4T1 and MCF-7; ER⁺ (estrogen-responsive) and MDA-MB231; ER⁻ (estrogen-unresponsive) in BC cells.⁴⁴ Tumor xenografts derived from the experimental mice treated with specific PEGylated leptin antagonists (PEG-LPrA2) were also investigated. A significant increase in leptin-mediated VEGF levels and VEGF/VEGFR2 upregulation were observed.⁷⁴

Interestingly, the association of tumor-associated leptin with VEGF regulation, compared with systemic leptin, was also determined. The ability of tumor stromal and non-cancerous cells such as fibroblasts, immune cells, and endothelial cells to produce VEGF is also impacted by leptin signaling. However, PEG-LPrA2 treatment in ER⁺ MCF-7 mice xenograft models showed no effect on plasma leptin levels, indicating that systemic leptin metabolism remained unaffected. No significant differences were reported in the body or carcass weights between normal-weight BC xenograft mice and PEG-LPrA2-treated mice.⁷⁵ In another study, leptin-induced transactivation of VEGFR2, proliferation, and angiogenic differentiation were reported in VEGF-deprived Human Umbilical Vein Endothelial Cells (HUVEC) in vitro. VEGFR2 (Tyr117) was phosphorylated independently through cyclo-oxygenase 2 (COX-2), p38 MAP, and AKT signaling pathways. PEG-LPrA2 treatment inhibited the induction of angiogenesis by blocking leptin and VEGFR2 in HUVEC cells.^76,77

Anagnostoulis et al, in their in vivo experiment, used a disk implantation technique in rats using an anti-leptin antibody. Local proliferation of VECs and blood vessel formation were observed with subcutaneous implantation of polyvinyl sponge disks containing leptin at concentrations ranging from 25 to 250 ng/mL. Increased activation of Akt and mTOR pathways with reduced activation of adenosine monophosphate-activated kinase (AMPK) and SIRT1 was also reported in isogeneic immunocompetent epithelial OC mice kept on a high-energy diet (HED) compared with those maintained on a calorie-restricted diet (CRD).⁷⁸ With the progression of extensive tumor formation at multiple organ sites, increased levels of leptin, insulin, insulin-like growth factor-1 (IGF-1), monocyte chemoattractant protein-1 (MCP-1), VEGF, and interleukin 6 (IL-6) were observed.⁷⁹

Estrogen-mediated pathways also influence the expression of both VEGF and leptin, particularly in BC and OC. VEGFR, OB-R, and ER, are co-expressed in BC and OC, contribute to the increasingly proliferative and angiogenic tumor phenotype.⁸⁰ Leptin synthesis may be influenced by estrogen in a tissue- and cell-type-specific manner, due to increased aromatase expression mediated by the transactivation of ER. Increased aromatase activity in adipose tissues, contributes to local estrogen biosynthesis and ER-dependent transcriptional activity.⁸¹ However, leptin synthesis and release by adipocytes and activation of ER signaling have also been observed in the presence of antiestrogens or in the absence of estrogens, complicating the process of tumor growth, differentiation, and proliferation.⁸² This interaction is relevant in postmenopausal obese women, having higher levels of adipose-derived leptin and estrogen which together may contribute to tumor aggressiveness and poor clinical prognosis.^83,84 Different BC and OC types and subtypes having differential VEGF and leptin expression and their association with clinicopathological features are summarized in Table 2.⁸⁵

Table 2.

Clinical and Preclinical Expression of VEGF and OB-Rb in Different Subtypes of Breast Cancer and Histological Subtypes of Ovarian Cancer

Cancer Type/Subtype	VEGF Expression	OB-Rb Expression	Association with Clinicopathological Features	Survival/Prognostic Significance	Refs
Breast cancer	Moderate VEGF expression	Moderate leptin receptor (OB-Rb) expression	Associated with hormone receptor positivity and a lower proliferative index	Generally favorable prognosis; lower angiogenic activity	[44]
Breast cancer	Elevated VEGF compared with luminal A	Increased OB-Rb expression	Higher Ki-67 index, enhanced proliferation, endocrine resistance	Reduced disease-free survival relative to luminal A	[85]
Breast cancer	High VEGF overexpression	Increased OB-Rb signaling	Correlates with HER2 amplification, aggressive angiogenic phenotype	Poor prognosis and increased metastatic risk	[76]
Triple-negative breast cancer	Strong VEGF expression	High OB-Rb expression	Enhanced angiogenesis, invasion, inflammatory signaling, and chemoresistance	Shorter overall survival and higher recurrence rates	[76]
High-grade serous ovarian carcinoma	Markedly elevated VEGF levels in the tumor and ascites	Increased leptin/OB-Rb signaling	Associated with ascites formation, advanced FIGO stage, and metastasis	Poor progression-free and overall survival	[85]
Ovarian clear cell carcinoma	Moderate-to-high VEGF expression	Variable OB-Rb expression	Hypoxia adaptation, chemoresistance, and endometriosis-associated origin	Poor response to platinum therapy	[71,84]
Mucinous ovarian carcinoma	Variable VEGF expression	Limited data on OB-Rb	Associated with KRAS mutations and a distinct molecular phenotype	Better prognosis in early stages; poor in metastatic disease	[82]
Endometrioid ovarian carcinoma	Moderate VEGF expression	Detectable OB-Rb expression	Linked with endometriosis-associated inflammation and PI3K activation	Intermediate prognosis; better than HGSOC	[82]

Therapeutic Targeting of the VEGF-Leptin Signaling Axis

The biological heterogeneity of BC and OC underscores the need for personalized treatment approaches. Obesity-associated tumors exhibit distinct metabolic and inflammatory characteristics that can influence their response to anti-angiogenic and endocrine therapies (Figure 3).³⁹ Advanced molecular profiling techniques, including single-cell sequencing and spatial transcriptomics, can enhance our understanding of how adipose tissue signaling and tumor hypoxia shape the VEGF-leptin network in individual patients.⁸⁶

Figure 3.

Anti-VEGF and anti-leptin signaling therapeutic modalities used to inhibit the development, growth, progression, and metastasis of breast and ovarian cancers by inhibiting the induction of hypoxia, VEGF signaling, neovascularization, and immune signaling pathways. This causes the tumor cells to be killed by the recruitment of immune cells that may release tumor-suppressing cytokines, chemokines, perforins, and granzymes. The red arrow indicates the induction of hypoxia, whereas the T-shaped inhibitory symbol (⊣) indicates inhibition or blockade of the indicated pathway. Under “Tumor Killing”, solid arrows indicate direct cytotoxic effects mediated by secreted effector molecules, such as perforin and granzymes, whereas dashed arrows indicate indirect immune-mediated antitumor effects on tumor cells.

Anti-VEGF Therapeutic Strategies

Targeted inhibition of VEGF-mediated angiogenesis is an established therapeutic approach for solid tumors. Bevacizumab, a humanized monoclonal antibody against VEGF-A, inhibits the interaction of VEGF with VEGFR-1 and VEGFR-2, and block VEGF-A signaling, thereby suppressing tumor angiogenesis and endothelial cell proliferation.⁸⁷ In OC, bevacizumab has demonstrated clinically relevant improvements in progression-free survival in both first-line therapy and recurrent disease. FDA has approved its use for patients with advanced or recurrent epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer; therefore, it is recommended as a treatment option in several clinical settings.⁸⁸ In contrast, the use of bevacizumab for metastatic BC is demonstrated as non-approved rather than an approved or established therapeutic approach, as its FDA approval was withdrawn in 2011.^89,90 In addition to monoclonal antibodies, multitarget tyrosine kinase inhibitors (TKIs) such as cediranib, pazopanib, and nintedanib have also been investigated for their potential anti-angiogenic activity in BC and OC. However, their mode of action differs as cediranib primarily targets VEGFR-1, VEGFR-2, and VEGFR-3, pazopanib blocks VEGFRs and other receptor tyrosine kinases, such as PDGFR and c-Kit, whereas nintedanib targets VEGFRs, PDGFR, and FGFR. Although none of these agents have received FDA approval yet.^91–94 Recent findings also support the concept of vascular normalization, according to which transient modulation of abnormal tumor vasculature can improves drug uptake, immune-cell infiltration, and response to systemic therapies.⁹⁵

Targeting Leptin Signaling

Compared with anti-VEGF therapy, direct inhibition of leptin signaling is still in its early phase of development. It represents a promising therapeutic approach, particularly for obesity-associated malignancies. However, to date, no clearly identifiable active clinical trial has specifically evaluated pharmacological inhibition of leptin or its receptor as an anticancer strategy in either BC or OC. Ob-R antagonists, neutralizing antibodies, peptide inhibitors, and small molecule inhibitors have demonstrated anti-proliferative and antiangiogenic activity in preclinical BC and OC models.⁹⁶ Leptin signaling contributes to tumor growth by activating the JAK/STAT3, PI3K/Akt, and MAPK/ERK signaling pathways. These pathways regulate proliferation, stem cell properties, metabolic adaptation, and resistance to apoptosis.⁹⁷ Experimental inhibition of leptin signaling has shown a reduction in VEGF expression, impairment of tumor angiogenesis, and suppression of metastatic activity. Obesity-associated cancers may exhibit an increased dependence on leptin-mediated oncogenic signaling, suggesting that leptin-targeted therapies could be of particular benefit to patients with metabolic disorders.⁹⁸

Combination Therapies

Increasing evidence suggests that the simultaneous inhibition of angiogenic and metabolic signaling pathways can provide greater therapeutic efficacy than monotherapies. Combination therapies with anti-VEGF agents and PARP inhibitors have demonstrated remarkable clinical activity in the treatment of OC.⁹⁹ For example, the combination of olaparib and cediranib has been evaluated in clinical trials and significantly improved progression-free survival in patients with recurrent, platinum-sensitive OC by combining synthetic lethality with angiogenesis blockade.¹⁰⁰ New therapeutic approaches are also exploring the integration of angiogenesis inhibitors with inhibitors targeting leptin signaling, STAT3, PI3K/Akt/mTOR pathway, and immune checkpoint molecules.¹⁰¹ These multidimensional approaches aim to overcome tumor heterogeneity, metabolic plasticity, and adaptive resistance mechanisms that often limit sustained treatment success.¹⁰² In obesity-related tumors, where inflammatory and metabolic signaling pathways are closely linked, combination therapies could represent a particularly effective strategy for disrupting the oncogenic VEGF-leptin network, providing a rationale for further evaluation of VEGF–leptin axis.¹⁰³ Targeted and combination therapeutic modalities are summarized in Table 3.

Table 3.

Therapeutic Agents and Strategies for Influencing the VEGF-Leptin Axis in BC and OC

Therapeutic Class	Representative Agents	Primary Mechanism	Clinical Status	References
Anti-VEGF monoclonal antibody	Bevacizumab	Neutralizes VEGF-A and inhibits VEGFR-mediated angiogenesis	FDA-approved for selected ovarian cancer; not FDA-approved for breast cancer	[88,90,100]
VEGFR tyrosine kinase inhibitors	Cediranib, Pazopanib, Nintedanib	Inhibition of VEGFR-1/2/3 by cediranib; VEGFRs, PDGFR, and c-Kit by pazopanib; VEGFRs, PDGFR, and FGFR by nintedanib	Phase II/III evaluation; no FDA approval for ovarian cancer and breast cancer	[91–93]
PARP inhibitor + anti-angiogenic therapy	Olaparib + Cediranib	Combined synthetic lethality and angiogenic blockade	Advanced clinical evaluation for ovarian cancer	[95,99,101]
Leptin signaling inhibitors	Experimental leptin receptor antagonists and peptide inhibitors	Suppression of Ob-R-mediated oncogenic signaling	Preclinical/early translational stage	[97,98]
HIF-targeted therapies	HIF-1α/HIF-2α inhibitors	Block hypoxia-induced angiogenic and metabolic adaptation	Preclinical/e clinical development	[96]

Challenges and Resistance Mechanisms

Despite the clinical success of anti-angiogenic therapies, sustained remissions are limited as tumors can rapidly develop adaptive resistance mechanisms. In BC and OC, inhibition of VEGF signaling often leads to intra-tumoral hypoxia, which paradoxically promotes tumor aggressiveness by activating HIF-1α and compensatory pro-angiogenic pathways.¹⁰³ As a result, tumor cells can restore vascular growth through alternative mediators such as FGF, PDGF, angiopoietins, and interleukin-mediated inflammatory signals.¹⁰⁴

Another major challenge is the pronounced metabolic plasticity of tumor cells. Under therapeutic stress, cancer cells undergo metabolic reprogramming that enables them to survive under hypoxic and nutrient-deficient conditions.¹⁰⁵ Activation of the PI3K/Akt/mTOR and STAT3 signaling pathways maintains tumor proliferation, promotes resistance to apoptosis, and improves cancer stem cell survival.¹⁰⁶ Leptin signaling is an important factor in treatment resistance, as it can maintain angiogenic and survival pathways even during VEGF inhibition. Elevated leptin levels promote VEGF expression, endothelial activation, and chemotherapy resistance via JAK/STAT3- and PI3K/Akt-mediated signaling pathways, while angiogenesis, metabolic phenotype, and immune composition, further lead to heterogeneous treatment responses.¹⁰⁷

Clinical and Biomarker Implications

VEGF and leptin have emerged as promising circulating and tissue-specific biomarkers in BC and OC. Elevated serum VEGF concentrations frequently correlate with increased tumor vascular density, elevated metastatic potential, and advanced disease stage.¹⁰⁸ In OC, VEGF levels are particularly elevated in patients with malignant ascites and correlate with tumor burden and peritoneal seeding.¹⁰⁹ Similarly, increased leptin expression and Ob-R activation have been observed in obesity-associated BC and OC, suggesting their involvement in tumorigenesis and progression.^110,111 Beyond their individual functions, combined VEGF and leptin measurements can enhance diagnostic precision by integrating angiogenic and metabolic signatures within the TME.¹¹² Several studies suggest that the simultaneous evaluation of adipokine and angiogenesis profiles can help to differentiate aggressive tumor phenotypes from less invasive disease stages. The clinical implementation remains limited by inter-patient variability, obesity-associated confounding factors, and the lack of standardized biomarker thresholds.^113,114

Future Directions and Conclusion

This manuscript uniquely integrates VEGF-leptin crosstalk with biomarker and therapeutic implications. The VEGF-leptin axis plays a central role in the integration of angiogenic, inflammatory, and metabolic signaling pathways in BC and OC. Future research should focus on biomarker-based studies incorporating circulating VEGF and leptin levels, body mass index (BMI), HIF-1α activity, and Ob-R expression to better identify patients who may benefit from targeted anti-angiogenic therapies.⁸⁴ In parallel, leptin-directed therapies, including Ob-R antagonists and inhibitors of the downstream STAT3 and PI3K/Akt signaling pathways, are increasingly being investigated, as these approaches have demonstrated promising antitumor effects in preclinical studies.¹⁰⁶ Combination approaches targeting VEGF signaling in addition to metabolic and inflammatory pathways could also help overcome resistance to anti-angiogenic therapies. Recent studies suggest that simultaneous inhibition of the HIF-1α, STAT3, and mTOR signaling pathways could improve therapeutic efficacy by limiting compensatory survival signals within the TME.¹¹⁴

Personalized treatment strategies that integrate angiogenic, metabolic, and immunological biomarkers could offer more sustainable clinical benefits than conventional standard therapies. The combination of anti-VEGF therapies with endocrine therapy, PARP inhibitors, or immune checkpoint inhibitors represents an important area of research. VEGF and leptin act as closely interrelated mediators of tumor progression in BC and OC. Through the coordinated activation of the PI3K/Akt, MAPK/ERK, JAK/STAT3, mTOR, and HIF-1α signaling pathways, the VEGF-leptin axis may promote angiogenesis, proliferation, metabolic adaptation, and metastasis. Increasing evidence suggests that obesity-associated hyperleptinemia further enhances these oncogenic processes and contributes to treatment resistance. As obesity rates rise globally, clarifying VEGF-leptin interactions is critical for advancing cancer therapy. Therapeutic strategies that simultaneously target angiogenic and metabolic pathways could offer improved possibilities for precise therapy in BC and OC. Advanced research must be conducted to overcome the lack of clinical trials for leptin inhibitors and the need for standardized biomarker thresholds.

Disclosure

The author reports no conflicts of interest in this work.