Angiogenic Growth Factors: Orchestrators of Tumour Angiogenesis

This review explores the integral role of angiogenic growth factors in tumour development, focusing on their diverse functions within the tumour microenvironment. Emphasising key players such as Vascular Endothelial Growth Factor (VEGF) and Basic Fibroblast Growth Factor (bFGF), the review discusses their involvement in orchestrating angiogenesis and sustaining tumour growth. Therapeutic interventions, notablyanti-VEGF therapies, have shown promise, yet challenges such as acquired resistance and angiogenic signalling heterogeneity persist. The review underscores the importance of precision medicine, advocating for personalised strategies tailored to individual tumour characteristics. Exploration of emerging frontiers introduces angiopoietins and Notch signalling as novel players, offering potential targets for refined therapeutic approaches. Additionally, the review highlights the intersection of angiogenesis and immune regulation, paving the way for innovative combination therapies. In conclusion, this concise overview emphasises the challenges and opportunities in understanding angiogenic growthfactors, showcasing their potential in personalised and targeted therapeutic strategies for improved cancer patient outcomes.

Angiogenesis, the formation of new blood vessels from pre-existing vasculature, is a fundamental biological process that plays a pivotal role in both physiological and pathological contexts. In the setting of tumor development, angiogenesis becomes a cornerstone for sustained growth and progression, as it facilitates the delivery of oxygen and nutrients essential for tumor survival and expansion. Moreover, the newly formed vasculature acts as a conduit for the dissemination of cancer cells, contributing to metastasis and the spread of malignancy. Central to this phenomenon are angiogenic growth factors, a diverse group of molecular mediators that orchestrate the intricate interplay of signals within the tumor microenvironment. These factors regulate key processes such as endothelial cell proliferation, migration, and differentiation, ensuring the establishment of a functional vascular network. Beyond their direct effects on vascular development, angiogenic growth factors also influence the tumor stroma, modulating the behavior of immune cells, fibroblasts, and other stromal components, which collectively shape the tumor ecosystem. This review seeks to illuminate the integral role of these growth factors in tumor angiogenesis, shedding light on their diverse functions and complex interactions. By exploring therapeutic avenues that target these pathways, this discussion aims to highlight both the challenges and opportunities in leveraging our understanding of angiogenesis for cancer treatment.

Tumor-Induced Angiogenesis: A Necessity for Growth

The induction of angiogenesis, defined as the formation of new blood vessels from pre- existing vasculature, is widely recognized as a hallmark of cancer progression. This process is indispensable for tumor development, allowing cancerous tissues to overcome the limitations of diffusion and establish a vascular network capable of supplying the growing tumor mass with oxygen and nutrients [1]. Beyond supporting the metabolic needs of the tumor, angiogenesis also facilitates the removal of metabolic waste products, creating a microenvironment conducive to tumor cell survival and proliferation. Angiogenic growth factors are pivotal mediators of this process, initiating and sustaining the angiogenic switch that drives vascularization within tumors [2]. Among these, Vascular Endothelial Growth Factor (VEGF) is considered the cornerstone of tumor angiogenesis, acting primarily on endothelial cells to promote their proliferation, migration, and survival. Basic Fibroblast Growth Factor (bFGF) further complements VEGF activity by enhancing the recruitment and activation of endothelial progenitor cells, as well as stimulating matrix remodeling to facilitate vascular sprouting.

While VEGF and bFGF have garnered significant attention, the process of tumor-induced angiogenesis is far more complex, involving a multitude of other growth factors. Platelet- Derived Growth Factor (PDGF) contributes to pericyte recruitment and vascular stabilization, enhancing the structural integrity of newly formed vessels. Transforming Growth Factor-β (TGF-β) plays a dual role, acting as both a pro- and anti-angiogenic factor depending on the context of its activation. Additionally, the Angiopoietin family of proteins, particularly Angiopoietin-1 (Ang-1) and Angiopoietin-2 (Ang-2), regulates vessel maturation and remodeling, adding further intricacy to the angiogenic signaling network [3]. Together, these factors form an intricate web of signals that tightly regulate angiogenesis within the tumor microenvironment. The redundancy and plasticity of these pathways not only under score the importance of angiogenesis in cancer progression but also highlight the challenges associated with targeting these processes therapeutically.

Dynamic Interactions in the Tumor Microenvironment

The tumor microenvironment represents a dynamic and complex ecosystem where cancer cells coexist and interact with a variety of non-cancerous cells, including immune cells, fibroblasts, endothelial cells, and extracellular matrix components. These interactions are not passive but involve continuous and intricate crosstalk, driving tumor progression and enabling the tumor to adapt to its surroundings. Central to this communication are angiogenic growth factors, which act as key mediators in shaping the microenvironment to support tumor growth and vascularization [4]. Angiogenic growth factors such as VEGF and bFGF establish a pro-angiogenic milieu within the tumor microenvironment, promoting the recruitment, proliferation, and activation of endothelial cells. This process is critical for the formation of a functional vascular network that sustains tumor expansion. Beyond their direct effects on endothelial cells, these growth factors influence the behavior of other stromal components, further enhancing angiogenesis and facilitating tumor survival and progression.

Tumor-associated macrophages (TAMs) play a particularly significant role in amplifying the angiogenic response. Recruited to the tumor site by chemokines and cytokines, TAMs become polarized towards a pro-tumor phenotype, releasing high levels of angiogenic factors such as VEGF, TGF-β, and interleukins. This contributes to a positive feedback loop, wherein TAMs and cancer cells mutually stimulate each other, exacerbating angiogenesis and tumor progression [5]. Similarly, cancer-associated fibroblasts (CAFs) secrete matrix metalloproteinases (MMPs), which remodel the extracellular matrix, facilitating the migration of endothelial cells and the sprouting of new blood vessels. The tumor microenvironment also harbors regulatory mechanisms that fine-tune angiogenesis, reflecting the adaptive nature of this ecosystem. Hypoxia, a common feature of solid tumors, acts as a potent driver of angiogenic factor production, ensuring that vascularization is prioritized under conditions of oxygen deprivation. Meanwhile, the interplay between various stromal cells and cancer cells contributes to the heterogeneity of angiogenesis, posing challenges for therapeutic targeting. This dynamic and multifaceted interaction underscores the complexity of tumor angiogenesis, revealing a tightly regulated system that is vital for tumor progression and metastasis. Understanding the roles of different components within this microenvironment is essential for developing more effective and targeted therapeutic interventions [5].

Therapeutic Approaches: Targeting the Angiogenic Switch

Anti-angiogenic Therapies: Progress and Challenges

The recognition of angiogenesis as a pivotal driver of tumor growth and metastasis has revolutionized the approach to cancer therapy, leading to the development of anti- angiogenic treatments. Among these, VEGF inhibitors, such as bevacizumab, have been at the forefront of clinical advancements, offering a targeted means of disrupting the vascular support system essential for tumor sustenance [6]. These therapies work by inhibiting the signaling pathways that promote angiogenesis, thereby restricting the tumor’s access to nutrients and oxygen. Despite initial successes, several challenges have emerged, limiting the long-term efficacy of anti-angiogenic treatments. One significant obstacle is acquired resistance, where tumors adapt to circumvent the effects of VEGF inhibition, often by activating alternative angiogenic pathways or exploiting redundant signaling mechanisms [7]. For instance, upregulation of other growth factors such as bFGF, PDGF, and Angiopoietins can compensate for VEGF inhibition, allowing tumors to sustain angiogenesis despite therapeutic intervention.

Additionally, the heterogeneity of tumor angiogenesis presents another layer of complexity, as individual tumors, and even regions within the same tumor, may rely on distinct angiogenic mechanisms. This variability underscores the necessity for more nuanced therapeutic strategies that can address the dynamic and multifactorial nature of tumor vascularization. Ongoing research is focused on identifying robust biomarkers to predict patient responses to anti-angiogenic agents, allowing clinicians to select the most appropriate therapeutic options for each individual [8]. Refinement of combination therapies, which pair anti-angiogenic treatments with other modalities such as chemotherapy or immunotherapy, is also underway to enhance efficacy and combat resistance.

Personalized Medicine in Angiogenesis Modulation

The heterogeneity of angiogenic signaling across different tumor types and subtypes highlights the importance of a personalized approach to treatment. Traditional one-size-fits- all strategies often fail to account for the unique molecular and genetic landscapes of individual tumors, resulting in suboptimal outcomes [9]. Precision medicine offers a transformative solution by tailoring anti-angiogenic therapies to align with the specific characteristics of a patient’s tumor. This approach relies heavily on biomarker-driven methodologies, which involve identifying molecular markers that predict responsiveness to particular treatments. For example, biomarkers such as VEGF levels, hypoxia-inducible factors (HIFs), and components of the extracellular matrix have been investigated as potential indicators of sensitivity to anti- angiogenic agents [10]. By leveraging such biomarkers, clinicians can stratify patients into subgroups more likely to benefit from specific interventions, thereby maximizing therapeutic efficacy while minimizing unnecessary side effects. Moreover, advances in genomics and proteomics are providing deeper insights into the genetic and proteomic alterations underpinning angiogenesis, enabling the development of more sophisticated diagnostic tools and therapeutic strategies. As research in this area progresses, the integration of personalized medicine into clinical practice holds the promise of delivering more precise and effective anti-angiogenic therapies, ultimately improving outcomes for cancer patients.

Exploring Novel Frontiers: Beyond VEGF

Angiopoietins and Notch Signaling: Emerging Players

Recent advancements in research have highlighted the pivotal roles of angiopoietins and Notch signaling in fine-tuning the angiogenic process, offering novel insights into the mechanisms governing vascular development [11]. Among the angiopoietins, Ang-2 has garnered significant attention for its unique role in destabilizing existing blood vessels, a prerequisite for angiogenic sprouting. This vessel destabilization disrupts vascular integrity, sensitizing the tumor vasculature to the effects of anti-angiogenic therapies [12]. Importantly, the interplay between Ang-2 and its receptor, Tie2, creates a dynamic regulatory axis that influences both vessel regression and angiogenesis. This dual functionality makes Ang-2 a promising target for therapeutic interventions aimed at modulating tumor angiogenesis more effectively. In parallel, the Notch signaling pathway has emerged as a critical regulator of vascular development, with its multifaceted role in angiogenesis now well-recognized [13]. Notch signaling can act as both a promoter and suppressor of angiogenesis, depending on the cellular context and interactions with other signaling pathways. For example, its pro- angiogenic effects are mediated through the induction of vascular sprouting, while its anti- angiogenic roles often involve the stabilization and maturation of newly formed vessels.

Understanding the molecular intricacies of Notch signaling, including its cross talk with VEGF and angiopoietins, holds immense potential for designing precise therapeutic strategies aimed at selectively targeting specific aspects of the angiogenic process [14]. The therapeutic exploration of angiopoietins and Notch signaling represents a significant frontier in angiogenesis research, offering opportunities to develop novel drugs that can complement existing VEGF-targeted therapies. By addressing the limitations of current treatments, such as resistance and heterogeneity, these emerging pathways could help achieve more robust and sustained anti-angiogenic responses.

Combining Angiogenesis Inhibitors with Immunotherapy

The interplay between angiogenesis and immune regulation in the tumor microenvironment has opened new avenues for combinatorial therapeutic approaches [15]. Angiogenesis, while facilitating tumor growth, also contributes to the suppression of anti- tumor immune responses by creating an immunosuppressive microenvironment. This is mediated through mechanisms such as the recruitment of regulatory immune cells and the inhibition of effector T-cell infiltration into tumors. Consequently, combining anti- angiogenic therapies with immunotherapy offers a compelling strategy to disrupt this interplay, enhancing the overall efficacy of cancer treatment [16]. Anti-angiogenic agents, by normalizing the tumor vasculature, can improve immune cell infiltration and function, thereby potentiating the effects of immunotherapies such as immune checkpoint inhibitors. For example, preclinical studies have demonstrated that VEGF blockade can enhance the activity of PD-1/PD-L1 and CTLA-4 inhibitors, leading to improved anti-tumor responses. Moreover, angiogenesis inhibition may reduce the recruitment of immunosuppressive cells like tumor-associated macrophages and regulatory T cells, further augmenting the immune response.

Clinical trials investigating the combination of angiogenesis inhibitors with immunotherapies are showing promise, with early results indicating improved efficacy and durability of treatment outcomes compared to monotherapy approaches [17]. These trials underscore the potential of this combinatorial strategy to overcome the limitations of current therapies, offering a more comprehensive and multifaceted approach to tackling tumor progression. As research progresses, optimizing the timing, dosing, and sequencing of these combinations will be crucial to maximize their therapeutic potential.

In unravelling the intricate web of angiogenic growth factors in tumor development, researchers and clinicians alike face both challenges and opportunities [18]. The complex interactions between various angiogenic pathways, along with the dynamic and ever- changing tumor microenvironment, pose significant obstacles in developing reliable therapeutic strategies. Anti-angiogenic therapies have certainly made considerable progress in recent years, showing promise in the treatment of several cancer types. However, the heterogeneous nature of angiogenic signaling, where tumors can adapt and develop resistance to single-target therapies, highlights the need for further investigation and innovation [19]. The development of combination therapies, integrating both angiogenesis inhibitors and other treatment modalities, is becoming an increasingly important area of focus. Furthermore, advances in precision medicine, where therapies are tailored based on genetic, molecular, and environmental factors, offer an exciting avenue for overcoming some of the limitations seen with traditional approaches. The convergence of these fields— novel target discovery, personalized treatment plans, and combinatorial strategies—holds great promise in unlocking more effective and tailored approaches to impede tumor angiogenesis. By better understanding the complex biology of angiogenesis, clinicians and researchers can work towards optimizing cancer therapies, ultimately improving outcomes for cancer patients and potentially providing more durable, long-term responses in the fight against cancer [20].

Conflicts of interest

The authorshave no conflicts of interestto declare.

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