β2 Adrenergic-Neurotrophin Feedforward Loop Promotes Pancreatic Cancer

Renz, Bernhard W.; Takahashi, Ryota; Tanaka, Takayuki; Macchini, Marina; Hayakawa, Yoku; Dantes, Zahra; Maurer, H. Carlo; Chen, Xiaowei; Jiang, Zhengyu; Westphalen, C. Benedikt; Ilmer, Matthias; Valenti, G.; Mohanta, Sarajo; Habenicht, Andreas J. R.; Middelhoff, Moritz; Chu, Timothy; Nagar, Karan; Tailor, Yagnesh; Casadei, Riccardo; Marco, Mariacristina Di; Kleespies, Axel; Friedman, Richard A.; Remotti, Helen; Reichert, Maximilian; Worthley, Daniel L.; Neumann, Jens; Werner, Jens; Iuga, Alina; Olive, Kenneth P.; Wang, Yichen

doi:10.1016/j.ccell.2018.10.010

Cited by 76 publications

(63 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As cancers develop, axonal networks form in and around the tumor stroma, providing signals that modulate cancer progression [21,75]. Clinical data show that cancer patients treated with β-blockade, which impairs sympathetic nerve functions, have improved survival, supporting the role of nerve activity in cancer progression [24,75,86].…”

Section: Discussionmentioning

confidence: 99%

“…In the last few decades, increasing evidence indicates that innervation plays an active role in cancer onset, progression, and metastatization [20][21][22][23][24][25][26][27]. Many classes of cancer are infiltrated by nerve fibers, and their presence is associated with poor prognosis [21][22][23].…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, experiments conducted on mice have shown that denervation of primary tumors results in a strong decrease in tumor growth and dissemination. These observations were first conducted on prostate cancers [25], but in recent years nerve dependence has been demonstrated for many classes of tumors, including gastric cancers [27], melanomas [20], pancreatic cancers [24,26], and head and neck squamous cell carcinomas [22,23]. In addition to driving cancer progression, nerve fibers are the mediators of cancer-associated pain [28,29].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Ameloblastomas Exhibit Stem Cell Potential, Possess Neurotrophic Properties, and Establish Connections with Trigeminal Neurons

Pagella

Catón

Meisel

et al. 2020

Cells

View full text Add to dashboard Cite

Ameloblastomas are locally invasive and aggressive odontogenic tumors treated via surgical resection, which results in facial deformity and significant morbidity. Few studies have addressed the cellular and molecular events of ameloblastoma onset and progression, thus hampering the development of non-invasive therapeutic approaches. Tumorigenesis is driven by a plethora of factors, among which innervation has been long neglected. Recent findings have shown that innervation directly promotes tumor progression. On this basis, we investigated the molecular characteristics and neurotrophic properties of human ameloblastomas. Our results showed that ameloblastomas express dental epithelial stem cell markers, as well as components of the Notch signaling pathway, indicating persistence of stemness. We demonstrated that ameloblastomas express classical stem cell markers, exhibit stem cell potential, and form spheres. These tumors express also molecules of the Notch signaling pathway, fundamental for stem cells and their fate. Additionally, we showed that ameloblastomas express the neurotrophic factors NGF and BDNF, as well as their receptors TRKA, TRKB, and P75/NGFR, which are responsible for their innervation by trigeminal axons in vivo. In vitro studies using microfluidic devices showed that ameloblastoma cells attract and form connections with these nerves. Innervation of ameloblastomas might play a key role in the onset of this malignancy and might represent a promising target for non-invasive pharmacological interventions.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Ameloblastomas Exhibit Stem Cell Potential, Possess Neurotrophic Properties, and Establish Connections with Trigeminal Neurons

Pagella

Catón

Meisel

et al. 2020

Cells

View full text Add to dashboard Cite

show abstract

“…β-adrenergic signaling induces NGF and BDNF to axonogenesis 287 Pancreatic ductal adenocarcinoma. β2 antagonists (ICI-118,551, propranolol).…”

Section: Anti-il10r Antibody Il-4ra-blocking Antibodymentioning

confidence: 99%

Tumor-induced neurogenesis and immune evasion as targets of innovative anti-cancer therapies

Cervantes‐Villagrana

Albores-García

Cervantes-Villagrana

et al. 2020

Sig Transduct Target Ther

137

104

View full text Add to dashboard Cite

Normal cells are hijacked by cancer cells forming together heterogeneous tumor masses immersed in aberrant communication circuits that facilitate tumor growth and dissemination. Besides the well characterized angiogenic effect of some tumor-derived factors; others, such as BDNF, recruit peripheral nerves and leukocytes. The neurogenic switch, activated by tumor-derived neurotrophins and extracellular vesicles, attracts adjacent peripheral fibers (autonomic/sensorial) and neural progenitor cells. Strikingly, tumor-associated nerve fibers can guide cancer cell dissemination. Moreover, IL-1β, CCL2, PGE 2 , among other chemotactic factors, attract natural immunosuppressive cells, including T regulatory (Tregs), myeloid-derived suppressor cells (MDSCs), and M2 macrophages, to the tumor microenvironment. These leukocytes further exacerbate the aberrant communication circuit releasing factors with neurogenic effect. Furthermore, cancer cells directly evade immune surveillance and the antitumoral actions of natural killer cells by activating immunosuppressive mechanisms elicited by heterophilic complexes, joining cancer and immune cells, formed by PD-L1/PD1 and CD80/CTLA-4 plasma membrane proteins. Altogether, nervous and immune cells, together with fibroblasts, endothelial, and bone-marrow-derived cells, promote tumor growth and enhance the metastatic properties of cancer cells. Inspired by the demonstrated, but restricted, power of anti-angiogenic and immune cell-based therapies, preclinical studies are focusing on strategies aimed to inhibit tumor-induced neurogenesis. Here we discuss the potential of anti-neurogenesis and, considering the interplay between nervous and immune systems, we also focus on anti-immunosuppression-based therapies. Small molecules, antibodies and immune cells are being considered as therapeutic agents, aimed to prevent cancer cell communication with neurons and leukocytes, targeting chemotactic and neurotransmitter signaling pathways linked to perineural invasion and metastasis.

show abstract

“…For instance, chronic neuropsychological stress promotes Kras-induced pancreatic tumorigenesis, driven by activated β2-adrenergic receptor signaling, nerve growth factor secretion, and upregulation of catecholamines. A successful combination therapy using tropomyosin receptor kinase inhibitor with gemcitabine was described in a pancreatic cancer animal model, but the rationale and mechanistic insight on the successful combination was not provided ( Renz et al, 2018a ). In ovarian carcinoma, a pioneering study showed that behavioral stress enhances tumor angiogenesis in vivo and thereby promotes malignant cell growth, which resulted from aberrant β-adrenergic activation of the cAMP-PKA signaling pathway ( Thaker et al, 2006 ).…”

Section: Regulation At the Central Levelmentioning

confidence: 99%

Systemic Regulation of Cancer Development by Neuro-Endocrine-Immune Signaling Network at Multiple Levels

Jiang

Zhang

et al. 2020

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

The overarching view of current tumor therapies simplifies cancer to a cell-biology problem in which neoplasms are caused solely by malignant cells and the exploration of carcinogenesis and tumor progression largely focuses on somatic mutations and other genetic abnormalities of cancer cells. The limited therapeutic response indicates that cancer is driven not only by endogenous oncogenic factors and reciprocal interactions within the tumor microenvironment, but also by complex systemic processes. Homeostasis is the fundamental premise of health, and is maintained by systemic regulation of neuro-endocrine-immune axis. Cancer is also a systemic disease that manifested by dysfunction of the nervous, endocrine, and immune systems. Multiple axes of regulation exist in cancer, including central-, organ-, and microenvironment-level manipulation. At each specific regulatory level, the tridirectional communication among the nervous, endocrine, and immune factors transmit flexible signaling to induce proliferation, invasion, reprogrammed metabolism, therapeutic resistance, and other malignant phenotypes of cancer cells, resulting in the extremely poor prognosis of this lethal disease. Understanding this coordinated signaling network will enable the development of new approaches for cancer treatment via behavioral and pharmacological interventions.

show abstract

β2 Adrenergic-Neurotrophin Feedforward Loop Promotes Pancreatic Cancer

Cited by 76 publications

References 0 publications

Ameloblastomas Exhibit Stem Cell Potential, Possess Neurotrophic Properties, and Establish Connections with Trigeminal Neurons

Ameloblastomas Exhibit Stem Cell Potential, Possess Neurotrophic Properties, and Establish Connections with Trigeminal Neurons

Tumor-induced neurogenesis and immune evasion as targets of innovative anti-cancer therapies

Systemic Regulation of Cancer Development by Neuro-Endocrine-Immune Signaling Network at Multiple Levels

Contact Info

Product

Resources

About