This coreceptor might be a heparan sulfate proteoglycan e. Slit2 signaling through Robo1 and Robo2 mediates pathological retinal neovacularisation. This attracting versus repellent action is typical for members of the axon guidance family. In the case of Slits it is at least partly caused by differential receptor activation. Robo1, which directly interacts with Slits, promotes endothelial motility. Thus, based on their altered expression in a wide variety of cancer types and their regulatory function on vascular networks, Slits and Robos might serve as targets for cancer treatment.
However, their bifunctionality, that is, opposite functions depending on the cellular circumstances, represents a major challenge.
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Like Slit proteins, semaphorins are multifaceted regulatory signals involved in physiological and pathological angiogenesis. As regulators of tumor angiogenesis, tumor growth, cancer cell invasiveness, and metastatic spreading, they are potential therapeutic targets in cancer. In vertebrates, the semaphorin family contains around 20 genes that are classified based on common structural features of the encoded proteins.
This domain is also present in the semaphorin receptors of the plexin family. The active forms of several class 3 and class 6 semaphorins are homodimers. Plexins are the main receptors for semaphorins, but a subset of the class 3 semaphorins requires the presence of obligate coreceptor molecules, called neuropilins Nrp1 and Nrp2. Sema3A is an inhibitor of developmental angiogenesis.
Some semaphorins seem to control the recruitment and activation of leukocytes. The receptor—ligand interactions are highly promiscuous. Classical forward signaling i. Reverse signaling occurs when a Class B ephrin mediates after interaction with its receptor signaling in the cell on which the ephrin is expressed. Of note, transmembrane semaphorins Classes 4 and 6 may also transduce reverse signals. Subsequent forward signaling through EphA2 stimulates angiogenesis and vascular permeability. Since , an increasing number of miRs has been identified that regulate the expression of angiogenic factors or interfere with angiogenic signaling pathways for an overview, see Table I and reviewed in 6.
MiRs targeting proangiogenic factors are typically downregulated in cancer, whereas angiogenic miRs reduce angiostatic proteins. As such, both can contribute to the angiogenic switch during cancer progression. Each of these miRs holds the potential to regulate several target mRNAs.
Normal Wound Healing and Tumor Angiogenesis as a Game of Competitive Inhibition
As such, the functions of this miR cluster are very diverse and cell type and context dependent. Further experimental evidence suggests that miRs are important components of cellular adaptation to hypoxia.
Expression of this hypoxamiR is greatly induced in pancreatic, breast, head and neck, lung, colon, and renal cell lines after exposure to hypoxia. The role of EC metabolism in tumor angiogenesis has been completely overlooked during the past 40 years. Indeed, activated ECs rapidly switch from quiescence to angiogenic sprouting and must be able to adjust their metabolism accordingly. Thus, metabolic changes may significantly impact EC behavior and activity. Accordingly, knockdown of PFKFB3 in ECs reduces vascular sprouting by impairing tip cell migration and stalk cell proliferation, without affecting the expression of angiogenic factors.
Glycolytic intermediates may also be shuttled into other metabolic pathways, including the pentose phosphate pathway PPP and hexosamine biosynthesis pathway HBP. Tumor ECs upregulate genes involved in nucleotide synthesis and shunt glucose metabolites to nucleotide pathways to assure sufficiently high nucleotide pools for cell duplication. MYC ablation impairs glycolysis, mitochondrial function, and proliferation of ECs. Besides glucose, fatty acids FAs represent an important fuel source for ECs.
Instead, FAO provides carbons for de novo nucleotide synthesis via the tricarboxylic acid TCA cycle, thereby promoting EC proliferation and sprouting angiogenesis. Its deficiency impairs sprouting and proliferation without altering ATP levels or oxygen consumption. In conclusion, recent data indicate that metabolic reprogramming, a crucial hallmark of cancer that shifts metabolic pathways to enable sustained growth of cancer cells, also applies to tumor ECs. However, it should be noted that energy production depends on nutrient availability.
As such, EC metabolism is modulated by the metabolic program of other cell types in the tumor microenvironment. Moreover, as novel mediators continue to be discovered, it is clear that the multifactorial nature of neovascularization requires tackling the process at different levels.
During the past 10 years, angiogenesis inhibiting drugs have been tested i in the adjuvant setting after surgical removal of the primary tumor to prevent local relapse or the growth of micrometastases or ii in the neoadjuvant setting to downsize nonresectable to potentially resectable tumors. Despite the increasing number of data and drug candidates, resistance to antiangiogenic therapy remains a challenging issue that is associated with variable success in the clinic and with poor prognosis for cancer patients.
Several mechanisms can account for this therapeutic failure. However, the majority of TKIs used to treat patients are multitargeting drugs that nevertheless failed to treat different types of tumors. Antiangiogenic as well as vascular disrupting agents VDAs , which cause acute hypoxia, trigger the recruitment of EPCs and immune cells to the tumor margins.
In myxofibrosarcoma patients, elevated numbers of neutrophils positively correlate with tumor MVD. Moreover, intratumoral infiltration of neutrophils is significantly associated with tumor grade in glioma patients. Despite their potential role in antitumor immunity, high frequencies of TAMs correlate with poor prognosis in most human cancers.
Tumor angiogenesis revisited: Regulators and clinical implications
Furthermore, many other stromal subpopulations may be present or recruited at the tumor site during tumor growth or in response to antiangiogenic treatment. In particular, immature myeloid cells or EPCs that produce growth factors or physically incorporate into tumor blood vessels have been detected in the tumor microenvironment, where they may foster resistance to antiVEGF therapy.
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As mentioned in Chapter 2, tumor vascularization may occur through different mechanisms Fig. IMG occurs in various tumor types, and is increased in relapsing tumors after irradiation or antiangiogenic treatment. Moreover, the mechanism of IMG is very different from sprouting, indicating that other therapeutic strategies will have to be followed. A prerequisite for the anticancer potential of antiangiogenic agents is the vascular dependence of tumors.
Some cancer cells are highly vessel dependent, whereas others can survive in more hypoxic regions of tumors, distal from tumor vessels. Several mechanisms may account for the vascular independence of tumor cells. After an initial regression, tumors became resistant and resumed growth in the absence of tumor angiogenesis. Distal cells located in avascular areas underwent metabolic reprogramming toward a hyperglycolytic state producing lactate, which was utilized by tumor cells in the vicinity of blood vessels for oxidative phosphorylation.
Altogether these observations confirm that, even if antiangiogenic therapy targets genetically stable ECs in the tumor vasculature, genetic alterations or metabolic switches that decrease the vascular dependence of tumor cells can influence the therapeutic response of tumors to this therapy. Hypoxia is one of the main features of solid tumors, and correlates with poor prognosis of cancer patients. Intratumoral hypoxia can confer chemoresistance by i affecting drug delivery and cellular uptake through associated acidity, ii upregulation of multidrug resistance protein MDR expression, or iii by the fact that a number of chemotherapeutics require oxygen to exert their cytotoxic activity.
The original paradigm of tumor growth stated that tumors cannot survive or grow in conditions of hypoxia, such as induced by antiangiogenic therapy. Consequently, cells that lack functional p53 are even more prone to further genomic instability, and potentially tumorigenesis, if they experience reoxygenation after acute exposure to hypoxia.
Hypoxia results in the activation of HIFs.
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These transcription factors are master regulators of O 2 homeostasis that mediate many transcriptional changes in response to low O 2 tension. Degradation involves recognition by prolyl hydroxylase domain PHD enzymes, binding to the von Hippel—Lindau VHL tumor suppressor protein, ubiquitination, and proteasomal degradation. Intratumoral neovessels are often abnormal, immature, and leaky, and expanding tumors are extremely demanding in terms of nutrients and oxygen. Since antiangiogenic compounds are thought to specifically target newly formed, rather than existing vessels or other normal cell types, no or only minor toxicity was anticipated.
However, the expanding use of drugs targeting the VEGF signaling pathway in cancer unveiled that these antiangiogenic treatments are often associated with a wide spectrum of toxicities. Some adverse effects are shared with conventional chemotherapeutic agents while others are unique and not typically observed with cytotoxic drugs.
One study associated bevacizumab with increased risk of death in combination with taxanes or platinum agents but not in combination with other agents. Besides bevacizumab, which targets VEGF, some mAbs exhibit antiangiogenic functions due to crosstalk between the signaling pathways that involve VEGF and other growth factors. Unlike antibodies and ligand trap molecules, TKIs Fig.
Due to similarities in the kinase domains, most TKIs offer multitarget activity, good response, and sometimes improved survival rates in phase III clinical trials. Nevertheless, TKIs have also been investigated in combination with chemotherapy, especially in advanced NSCLC, showing clinical benefits in some studies, but failing to prolong overall survival in others. However, preclinical data provided evidence that cotargeting signaling by multiple proangiogenic factors is necessary to obtain an efficient and durable effect on tumor angiogenesis and growth, implying that multitarget inhibition might be a promising anticancer strategy.
VDAs target the already existing vessels in the tumor environment, thereby provoking a rapid collapse of the tumor vasculature leading to necrosis at the tumor core reviewed in The clinical success of VDAs depends on the elimination of the viable tumor rim that is resistant to these compounds. Tumor angiogenesis also influences immune suppression, and angiogenic factors regulate immune cell trafficking across tumor endothelia. These studies will provide the basis for further investigations regarding the interactions among angiogenic factors, blood vessel formation, immune regulation, and microenvironment, eventually paving the way for therapeutic exploitation of new drug combinations.
The tumor vasculature is characterized by increased vessel permeability and high interstitial fluid pressure as a consequence of its tortuous and chaotic structure, scarce pericyte coverage, and discontinuous BM. Instead of vascular disruption, vessel normalization aims to increase partial oxygen pressure and perivascular cell coverage in the tumor.
This can be obtained through pruning and remodeling of abnormal tumor vessels, leading to vessels resembling normal tissue vasculature in terms of structure and function Fig. Moreover, bevacizumab improved response to chemotherapy, especially in patients with a high pretreatment MVD, suggesting that this approach is only beneficial in highly vascularized tumors. Platt and Jerald E. Tarapore and Yizeng Yang.
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Tumor Angiogenesis Regulators 1st Edition. Resources to the following titles can be found at www. What are VitalSource eBooks? For Instructors Request Inspection Copy. The emphasis of this book is on mechanisms and pathways regulating the expression and actions of classical and novel tumor angiogenesis regulators. The contributors discuss their underlying biology as well as anti-angiogenic drugs currently in use to fight different cancers.
Tumor Angiogenesis Regulators
The book provides an insight on how factors such as obesity, diabetes, and other metabolic disorders can influence the development and growth of cancer. It is of significant interest not only to oncologists but also to a wide range of medical practitioners and researchers. Outram and S. Laronna S. Platt and Jerald E. We provide complimentary e-inspection copies of primary textbooks to instructors considering our books for course adoption.
Most VitalSource eBooks are available in a reflowable EPUB format which allows you to resize text to suit you and enables other accessibility features. Where the content of the eBook requires a specific layout, or contains maths or other special characters, the eBook will be available in PDF PBK format, which cannot be reflowed.