Tumor angiogenesis: causes, consequences, challenges and opportunities (original) (raw)

Inducing Angiogenesis, A Key Step in Cancer Vascularization, and Treatment Approaches

2020

Angiogenesis is a term that describes the formation of new blood and lymphatic vessels from a pre-existing vasculature. This allows tumour cells to acquire sustenance in the form of nutrients and oxygen and the ability to evacuate metabolic waste. As one of the hallmarks of cancer, angiogenesis has been studied extensively in animal and human models to enable better understanding of cancer biology and the development of new anti-cancer treatments. Angiogenesis plays a crucial role in the process of tumour genesis, because solid tumour need a blood supply if they are to grow beyond a few millimeters in size. On the other hand, there is growing evidence that some solid tumour exploit existing normal blood supply and do not require a new vessel formation to grow and to undergo metastasis. This review of the literature will present the current understanding of this intricate process and the latest advances in the use of angiogenesis-targeting therapies in the fight against cancer.

Alternative Vascularization Mechanisms in Cancer

The American Journal of Pathology, 2007

Although cancer cells are not generally controlled by normal regulatory mechanisms, tumor growth is highly dependent on the supply of oxygen, nutrients, and host-derived regulators. It is now established that tumor vasculature is not necessarily derived from endothelial cell sprouting; instead, cancer tissue can acquire its vasculature by co-option of pre-existing vessels, intussusceptive microvascular growth, postnatal vasculogenesis, glomeruloid angiogenesis, or vasculogenic mimicry. The best-known molecular pathway driving tumor vascularization is the hypoxia-adaptation mechanism. However, a broad and diverse spectrum of genetic aberrations is associated with the development of the "angiogenic phenotype." Based on this knowledge, novel forms of antivascular modalities have been developed in the past decade. When applying these targeted therapies , the stage of tumor progression , the type of vascularization of the given cancer tissue , and the molecular machinery behind the vascularization process all need to be considered. A further challenge is finding the most appropriate combinations of antivascular therapies and standard radio-and chemotherapies. This review intends to integrate our recent knowledge in this field into a rational strategy that could be the basis for developing effective clinical modalities using antivascular therapy for cancer.

III. Angiogenesis: Complexity of Tumor Vasculature and Microenvironment

Current Pharmaceutical Design

Vascular system plays critical roles in tumor progression and metastasis. Tumor vessels generally sprout from preexisting vascular cells. In addition, pluripotent progenitor cells also participate in tumor neovascularization. The latter populations include endothelial progenitor cells, hematopoietic stem cells and mesenchymal stem cells that are stimulated and attracted into the lesion. Recent studies on tumor microenvironment have disclosed that BM (bone marrow)-derived progenitor cells contain unique subpopulations that do not become fully-differentiated vascular constituents; instead, they show the nature of immature myeloid or mesenchymal lineage, and they enhance tumor angiogenic milieu in close contact with tumor vessels. BM-derived cells also migrate into pre-metastatic niche and stimulate vascular beds of distant organ for attracting circulating tumor cells. Currently, several antiangiogenic molecules are under clinical trials and they are expected to improve overall prognosis. Humanized monoclonal antibody bevacizumab specifically targeting VEGF (vascular endothelial growth factor), and several tyrosine kinase inhibitors targeting VEGF receptors-mediated pathways are the most widely studied agents in several types of advanced cancers. It is obvious that VEGF contributes to tumor neovascularization as a mastermind molecule. On the other hand, the mechanism has also been elucidated how tumors evade VEGF targeting therapies. To establish safer and more effective antiangiogenic therapies, it is important to understand the crosscommunication between tumors and hosts in proinflammatory milieu. In this review, we discuss features of tumor angiogenic vessels and their microenvironment. Recent topics on the contribution of BM-derived cells, complexities of VEGFtargeting approaches, and chemoattractants that activate tumor vascular beds are summarized.

Molecular mechanisms of tumor angiogenesis and tumor progression

Journal of neuro-oncology

The formation of new blood vessels (angiogenesis) is crucial for the growth and persistence of primary solid tumors and their metastases. Furthermore, angiogenesis is also required for metastatic dissemination, since an increase in vascular density will allow easier access of tumor cells to the circulation. Induction of angiogenesis precedes the formation of malignant tumors, and increased vascularization seems to correlate with the invasive properties of tumors and thus with the malignant tumor phenotype. In the last few years, the discovery and characterization of tumor-derived angiogenesis modulators greatly contributed to our understanding of how tumors regulate angiogenesis. However, although angiogenesis appears to be a rate-limiting event in tumor growth and metastatic dissemination, a direct connection between the induction of angiogenesis and the progression to tumor malignancy is less well understood. In this review, we discuss the most recent observations concerning the m...

Anti-angiogenic therapy for cancer: current progress, unresolved questions and future directions

Tumours require a vascular supply to grow and can achieve this via the expression of pro-angiogenic growth factors, including members of the vascular endo-thelial growth factor (VEGF) family of ligands. Since one or more of the VEGF ligand family is overexpressed in most solid cancers, there was great optimism that inhibition of the VEGF pathway would represent an effective anti-angiogenic therapy for most tumour types. Encouragingly, VEGF pathway targeted drugs such as bevacizumab, sun-itinib and aflibercept have shown activity in certain settings. However, inhibition of VEGF signalling is not effective in all cancers, prompting the need to further understand how the vasculature can be effectively targeted in tumours. Here we present a succinct review of the progress with VEGF-targeted therapy and the unresolved questions that exist in the field: including its use in different disease stages (metastatic, adjuvant, neoadjuvant), interactions with chemotherapy, duration and scheduling of therapy, potential predictive biomarkers and proposed mechanisms of resistance, including paradoxical effects such as enhanced tumour aggressiveness. In terms of future directions, we discuss the need to delineate further the complexities of tumour vascularisation if we are to develop more effective and personalised anti-angiogenic therapies.

Vascular targeted therapies in oncology

Cell and Tissue Research, 2009

Neovascularization is intimately involved in tumor survival, progression, and spread, factors known to contribute significantly to treatment failures. Thus, strategies targeting the tumor blood vessel support network may offer not only unique therapeutic opportunities in their own right, but also novel means of enhancing the efficacies of conventional anticancer treatments. This article reviews one such therapeutic approach directed at the tumor blood vessel support network. Vascular disrupting therapies seek the destruction of the established neovasculature of actively growing tumors. The goal of these therapies is to cause a rapid and catastrophic shutdown in the vascular function of the tumor in order to arrest the blood flow and produce tumor cell death as a result of oxygen and nutrient deprivation and the build up of waste products.

Angiogenesis in cancer - general pathways and their therapeutic implications

Journal of B.U.ON. : official journal of the Balkan Union of Oncology

A vast amount of data shows that angiogenesis has a pivotal role in tumor growth, progression, invasiveness and metastasis. This is a complex process involving essential signaling pathways such as vascular endothelial growth factor (VEGF) and Notch in vasculature, as well as additional players such as bone marrow-derived endothelial progenitor cells. Primary tumor cells, stromal cells and cancer stem cells strongly influence vessel growth in tumors. Better understanding of the role of the different pathways and the crosstalk between different cells during tumor angiogenesis are crucial factors for developing more effective anticancer therapies. Targeting angiogenic factors from the VEGF family has become an effective strategy to inhibit tumor growth and so far the most successful results are seen in metastatic colorectal cancer (CRC), renal cell carcinoma (RCC) and non-small cell lung cancer (NSCLL). Despite the initial enthusiasm, the angiogenesis inhibitors showed only moderate su...

Tumor Neovascularization and Developments in Therapeutics

Cancers, 2019

Tumors undergo fast neovascularization to support the rapid proliferation of cancer cells. Vasculature in tumors, unlike that in wound healing, is immature and affects the tumor microenvironment, resulting in hypoxia, acidosis, glucose starvation, immune cell infiltration, and decreased activity, all of which promote cancer progression, metastasis, and drug resistance. This innate defect of tumor vasculature can however represent a useful therapeutic target. Angiogenesis inhibitors targeting tumor vascular endothelial cells important for angiogenesis have attracted attention as cancer therapy agents that utilize features of the tumor microenvironment. While angiogenesis inhibitors have the advantage of targeting neovascularization factors common to all cancer types, some limitations to their deployment have emerged. Further understanding of the mechanism of tumor angiogenesis may contribute to the development of new antiangiogenic therapeutic approaches to control tumor invasion and...