Double Attack on Tumors by Targeting With Guidance Molecules

Weick, Anja; Augustin, Hellmut G.

doi:10.1161/atvbaha.110.222240

Cited by 3 publications

(7 citation statements)

References 13 publications

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“…For example, β-blockers are being considered to be a novel adjuvant to existing therapeutic strategies in clinical oncology (73). Finally, as important modulators in the nervous system and cancer, neurotrophic factors, neuropilins, axonal guidance molecules, neurotransmitters and their receptors are being considered to exploit new drugs to be used to treat metastasis (78,82,111,165,234,246–250). …”

Section: Clinical and Biological Implications For The Role Of Nervousmentioning

confidence: 99%

Role of the nervous system in cancer metastasis

Sun

Gao

2013

Oncology Letters

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The notion that tumors lack innervation was proposed several years ago. However, nerve fibers are irregulatedly found in some tumor tissues. Their terminals interaction with cancer cells are considered to be neuro-neoplastic synapses. Moreover, neural-related factors, which are important players in the development and activity of the nervous system, have been found in cancer cells. Thus, they establish a direct connection between the nervous system and tumor cells. They modulate the process of metastasis, including degradation of base membranes, cancer cell invasion, migration, extravasation and colonization. Peripheral nerve invasion provides another pathway for the spread of cancer cells when blood and lymphatic metastases are absent, which is based on the interactions between the microenvironments of nerve fibers and tumor cells. The nervous system also modulates angiogenesis, the tumor microenvironment, bone marrow, immune functions and inflammatory pathways to influence metastases. Denervation of the tumor has been reported to enhance cancer metastasis. Stress, social isolation and other emotional factors may increase distant metastasis through releasing hormones from the brain, the hypothalamic-pituitary-adrenal axis and autonomic nervous system. Disruption of circadian rhythms will also promote cancer metastasis through direct and indirect actions of the nervous system. Therefore, the nervous system plays an important role in cancer metastasis.

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Section: Clinical and Biological Implications For The Role Of Nervousmentioning

confidence: 99%

Role of the nervous system in cancer metastasis

Sun

Gao

2013

Oncology Letters

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“…29 Since VEGF-targeted therapies have been shown to have limited efficacy, the concept of targeting stromal cells in general has been brought to the forefront. 30 Guidance molecules including semaphorins, ephrins, netrins, and slit, well known to influence neuronal guidance, also have a role in vascular remodeling. 31 More specifically, semaphorins interact with Neuropilin-1 (NRP1) receptors to inhibit migration of endothelial and tumor cells alike.…”

Section: The Tumor Vasculaturementioning

confidence: 99%

“…50 Because NRP1 and 2 are expressed on both tumor and endothelial cells, it has been demonstrated that Sema3A can be used to target cancer with a dual approach. 30 The interacting region of NRP with VEGF is distinct from that of semaphorins, and it is mediated via its b1b2 extracellular domains. 51,52 NRP1 has a short cytoplasmic tail with a single PDZbinding domain, but it contains no inherent enzymatic activity, and its ability to signal on its own is not clear at this point.…”

Section: Monographsmentioning

confidence: 99%

Molecular Mechanisms of Tumor Angiogenesis

2011

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Tumors have been recently recognized as aberrant organs composed of a complex mixture of highly interactive cells that in addition to the cancer cell include stroma (fibroblasts, adipocytes, and myofibroblasts), inflammatory (innate and adaptive immune cells), and vascular cells (endothelial and mural cells). While initially cancer cells co-opt tissue-resident vessels, the tumor eventually recruits its own vascular supply. The process of tumor neovascularization proceeds through the combined output of inductive signals from the entire cellular constituency of the tumor. During the last two decades, the identification and mechanistic outcome of signaling pathways that mediate tumor angiogenesis have been elucidated. Interestingly, many of the genes and signaling pathways activated in tumor angiogenesis are identical to those operational during developmental vascular growth, but they lack feedback regulatory control and are highly affected by inflammatory cells and hypoxia. Consequently, tumor vessels are abnormal, fragile, and hyperpermeable. The lack of hierarchy and inconsistent investment of mural cells dampen the ability of the vessels to effectively perfuse the tumor, and the resulting hypoxia installs a vicious cycle that continuously perpetuates a state of vascular inefficiency. Pharmacological targeting of blood vessels, mainly through the VEGF signaling pathway, has proven effective in normalizing tumor vessels. This normalization improves perfusion and distribution of chemotherapeutic drugs with resulting tumor suppression and moderate increase in overall survival. However, resistance to antiangiogenic therapy occurs frequently and constitutes a critical barrier in the inhibition of tumor growth. A concrete understanding of the chief signaling pathways that stimulate vascular growth in tumors and their cross-talk will continue to be essential to further refine and effectively abort the angiogenic response in cancer.

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“…Recently, analyses of the angiogenic processes led to the identification of new proteins involved in the migration of ECs (summarized in table 1). These new antiangiogenic strategies could have a special role when combined with VEGF inhibition, maybe to overcome antiangiogenic resistance [41]. In which tumor stage these new antiangiogenic strategies should be incorporated is not yet clear.…”

Section: Discussionmentioning

confidence: 99%

“…2 Guidance molecules inhibit tumor progression by several ways. Adapted from Weick et al [41]. Thereby, semaphorins induce direct apoptotic effects on tumor cells.…”

Section: Robo Receptors Stabilize the Angiogenic Network Counteractinmentioning

confidence: 99%

New Antiangiogenic Strategies beyond Inhibition of Vascular Endothelial Growth Factor with Special Focus on Axon Guidance Molecules

Pircher¹,

Wellbrock

Fiedler

et al. 2014

Oncology

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Since the approval of the first antiangiogenic agent bevacizumab, a neutralizing antibody against the vascular endothelial growth factor (VEGF), antiangiogenic therapies augmented the standard armamentarium of anticancer therapies and proved their clinical efficacy. Nevertheless, antiangiogenic strategies could not fulfill the expected hopes. In clinical routine, therapy responses to antiangiogenic therapies were mostly transient and most of the patients developed evasive resistance mechanisms during therapy. Further, no predictive biomarker for therapy response could be developed, hampering the clinical development of these agents and triggering skepticism. In the past years, knowledge on the biology of angiogenesis increased and the role of tumor hypoxia was better characterized and identified as the driver for angiogenic regulation mechanisms. Besides VEGF, new angiogenic and antiangiogenic factors were characterized and the process of endothelial cell migration, proliferation and vessel formation was better elucidated. Thus, a strong connection to neural development and axon guidance molecules like netrins, Slit proteins, semaphorins, ephrins and their cognate receptors UNC5, Robo1-4, neuropilin and EphB was identified. The aim of this review is to present the importance of these axon guidance molecules with special focus on Robo4 and semaphorins in tumor angiogenesis and to highlight their value as potential targets for new antiangiogenic therapies.

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Double Attack on Tumors by Targeting With Guidance Molecules

Cited by 3 publications

References 13 publications

Role of the nervous system in cancer metastasis

Role of the nervous system in cancer metastasis

Molecular Mechanisms of Tumor Angiogenesis

New Antiangiogenic Strategies beyond Inhibition of Vascular Endothelial Growth Factor with Special Focus on Axon Guidance Molecules

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