bims-netuvo 2021-11-21 papers

Oncogene. 2021 Nov 16.

Tumor innervation is triggered by endoplasmic reticulum stress.

Chen Chen Jiang, Mark Marsland, Yufang Wang, Amiee Dowdell, Edward Eden, Fangfang Gao, Sam Faulkner, Phillip Jobling, Xiang Li, Lihua Liu, Zhangyu He, Hubert Hondermarck.

Nerve infiltration in the tumor microenvironment is emerging as a promoter of cancer progression that could be targeted in therapies, but the mechanisms initiating tumor innervation remain to be elucidated. Here we report that endoplasmic reticulum (ER) stress in cancer cells is transmitted to neuronal cells, resulting in neurite outgrowth and tumor innervation. In vitro, the induction of ER stress in various human cancer cells resulted in the synthesis and release of the precursor for brain-derived neurotrophic factor (proBDNF) through a mechanism dependent on the transcription factor X-box binding protein 1 (XBP1). Cancer cell-released proBDNF was found to mediate the transmission of ER stress to neurons, resulting in the stimulation of neurite outgrowth. Next-generation sequencing indicated the increased expression of the Egl-9 family hypoxia inducible factor 3 (EGLN3) that was mediated by c-MYC and necessary to neurite outgrowth induced by proBDNF. In orthotopic tumor xenograft, ER stress stimulated XBP1 and proBDNF expression as well as tumor innervation. Anti-proBDNF antibody inhibited both tumor innervation and cancer progression induced by ER stress. Interestingly, the chemotherapeutic drug 5-Fluorouracil (5-FU) was found to induce ER stress and tumor innervation, and this effect was inhibited by anti-proBDNF antibody. Finally, in human tumors, cancer tissues with nerve infiltration expressed high XBP1 and proBDNF while EGLN3 was upregulated in infiltrated nerves. This study reveals that ER stress participates in tumor innervation through the release of proBDNF and that targeting this pathway could be used in future therapies.

DOI: https://doi.org/10.1038/s41388-021-02108-6

Eur J Pharmacol. 2021 Nov 11. pii: S0014-2999(21)00782-2. [Epub ahead of print]913 174626

Parasympathetic, but not sympathetic denervation, suppressed colorectal cancer progression.

Shirin Sadighparvar, Saber Ghazizadeh Darband, Firouz Ghaderi-Pakdel, Ainaz Mihanfar, Maryam Majidinia.

Disruption in the nerve-tumor interaction is now considered as a possible anticancer strategy for treating various cancer types, particularly colorectal cancer. However, the underlying mechanisms are not still fully understood. Therefore, the present study aimed to evaluate the effects of sympathetic and parasympathetic denervation on the inhibition of colorectal cancer progression in early and late phases and assess the involvement of nerve growth factor in denervation mediated anticancer effects. One-hundred and fifty male Wistar rats were assigned into 15 groups. Seven groups comprising the control group, 1,2-dimethylhydrazine (DMH) group, sympathetic denervation group (celiac-mesenteric ganglionectomy and guanethidine sulphate administration), parasympathetic denervation group (vagotomy and atropine administration), and combination group were used in the early-stage protocol. For the late-stage protocol, eight groups comprising the control, DMH, surgical and pharmacological sympathetic and parasympathetic denervation groups, combination group, and 5-flourouracil group were considered. After 8 weeks, sympathetic and parasympathetic denervation significantly reduced ACF numbers in rats receiving DMH. On the other hand, in the late stages, parasympathetic but not sympathetic denervation resulted in significant reductions in tumor incidence, tumor volume and weight, cell proliferation (indicated by reduced immunostaining of PCNA and ki-67), and angiogenesis (indicated by reduced immunostaining of CD31 and VEGF expression levels), and downregulated NGF, β2 adrenergic, and M3 receptors. It can be concluded that parasympathetic denervation may be of high importance in colon carcinogenesis and suggested as a possible therapeutic modality in late stages of colorectal cancer.

Keywords: Autonomous nervous system; Colorectal cancer; DMH; Denervation; Nerve growth factor

DOI: https://doi.org/10.1016/j.ejphar.2021.174626

Acta Neuropathol Commun. 2021 Nov 16. 9(1): 183

Chemogenetic modulation of sensory neurons reveals their regulating role in melanoma progression.

Pedro A C Costa, Walison N Silva, Pedro H D M Prazeres, Caroline C Picoli, Gabriela D A Guardia, Alinne C Costa, Mariana A Oliveira, Pedro P G Guimarães, Ricardo Gonçalves, Mauro C X Pinto, Jaime H Amorim, Vasco A C Azevedo, Rodrigo R Resende, Remo C Russo, Thiago M Cunha, Pedro A F Galante, Akiva Mintz, Alexander Birbrair.

Sensory neurons have recently emerged as components of the tumor microenvironment. Nevertheless, whether sensory neuronal activity is important for tumor progression remains unknown. Here we used Designer Receptors Exclusively Activated by a Designer Drug (DREADD) technology to inhibit or activate sensory neurons' firing within the melanoma tumor. Melanoma growth and angiogenesis were accelerated following inhibition of sensory neurons' activity and were reduced following overstimulation of these neurons. Sensory neuron-specific overactivation also induced a boost in the immune surveillance by increasing tumor-infiltrating anti-tumor lymphocytes, while reducing immune-suppressor cells. In humans, a retrospective in silico analysis of melanoma biopsies revealed that increased expression of sensory neurons-related genes within melanoma was associated with improved survival. These findings suggest that sensory innervations regulate melanoma progression, indicating that manipulation of sensory neurons' activity may provide a valuable tool to improve melanoma patients' outcomes.

Keywords: Chemogenetics; Melanoma; Neuronal activity; Sensory neurons; Tumor microenvironment

DOI: https://doi.org/10.1186/s40478-021-01273-9

Laryngoscope. 2021 Nov 19.

Clinical Perineural Invasion and Immunotherapy for Head and Neck Cutaneous Squamous Cell Carcinoma.

Michael P Wu, Katherine L Reinshagen, Mary B Cunnane, Sophia Z Shalhout, Howard L Kaufman, David Miller, Kevin S Emerick.

OBJECTIVES/HYPOTHESIS: To describe outcomes of advanced head and neck cutaneous squamous cell carcinoma (cSCC) with clinical perineural invasion (cPNI) treated with immune checkpoint inhibitor (ICI) therapy, and to describe post-treatment radiographic findings in the context of clinical response to treatment using a new grading system.
STUDY DESIGN: Retrospective chart review.
METHODS: Retrospective chart review was performed for 11 patients treated with ICI for head and neck cSCC with cPNI of large named nerves. The primary outcome was response to treatment as defined by radiographic and clinical evidence. Clinical responses were defined as improvement in symptoms of neuropathic pain, hypoesthesia, nerve weakness, or decrease in visible tumor. Imaging studies were graded based on a new classification system for perineural invasion and reviewed by two neuroradiologists since RECISTv1.1 is inadequate to adjudicate response in these patients.
RESULTS: Nine (82%) patients had radiographic perineural disease control on ICI. Eight patients had improved radiographic perineural disease and one had stable disease. Of these, complete resolution of radiographic evidence of perineural disease was seen in only one patient. Seven (64%) patients had clinical responses, with either improved or stable radiographic disease.
CONCLUSIONS: ICI therapy is a viable treatment option for head and neck cSCC with cPNI. Radiographic and clinical evidence of response correlate well, with improvement in neuropathic pain being the most sensitive clinical marker of response. Even with favorable findings on repeat imaging and stable clinical course, complete resolution of perineural thickening and enhancement is rare. A grading system for classifying changes in perineural disease over time is proposed.
LEVEL OF EVIDENCE: 4 Laryngoscope, 2021.

Keywords: Perineural invasion; Response Evaluation Criteria in Solid Tumors; head and neck cutaneous squamous cell carcinoma; immune checkpoint inhibitors; perineural spread

DOI: https://doi.org/10.1002/lary.29953

Cancer Med. 2021 Nov 18.

Cutaneous squamous cell carcinoma staging may influence management in users: A survey study.

Vishal A Patel, Catherine McCullum, Andrew D Sparks, Chrysalyne D Schmults, Sarah T Arron, Anokhi Jambusaria-Pahlajani.

PURPOSE: This study aims to determine whether there is consensus regarding staging and management of cutaneous squamous cell carcinoma (CSCC) across the various specialties that manage this disease.
MATERIALS AND METHODS: A survey regarding CSCC high-risk features, staging, and management was created and emailed to cutaneous oncology experts including dermatology, head and neck surgery/surgical oncology, radiation oncology, and medical oncology.
RESULTS: One hundred fifty-six (46%) of 357 invited physicians completed the survey. Depth of invasion (92%), perineural invasion (99%), histologic differentiation (85%), and patient immunosuppression (90%) achieved consensus (>80%) as high-risk features of CSCC. Dermatologists were more likely to also choose clinical tumor diameter (79% vs. 54%) and histology (99% vs. 66%) as a high-risk feature. Dermatologists were also more likely to utilize the Brigham and Women's Hospital (BWH) staging system alone or in conjunction with American Joint Committee on Cancer (AJCC) (71%), whereas other cancer specialists (OCS) tend to use only AJCC (71%). Respondents considered AJCC T3 and higher (90%) and BWH T2b and higher (100%) to be high risk and when they consider radiologic imaging, sentinel lymph node biopsy, post-operative radiation therapy, and increased follow-up. Notably, a large number of respondents do not use staging systems or tumor stage to determine treatment options beyond surgery in high-risk CSCC.
CONCLUSION: This survey study highlights areas of consensus and differences regarding the definition of high-risk features of CSCC, staging approaches, and management patterns between dermatologists and OCS. High-risk CSCC is defined as, but not limited to, BWH T2b and higher and AJCC T3 and higher, and these thresholds can be used to identify cases for which treatment beyond surgery may be considered. Dermatologists are more likely to utilize BWH staging, likely because BWH validation studies showing advantages over AJCC were published in dermatology journals and discussed at dermatology meetings. Additional data are necessary to develop a comprehensive risk-based management approach for CSCC.

Keywords: American Joint Committee on Cancer Staging System; Brigham and Women Staging System; depth of tumor; high-risk cutaneous squamous cell carcinoma; high-risk tumor features; histologic differentiation; immunosuppression; perineural invasion; skin cancer; staging criteria; tumor diameter; tumor location

DOI: https://doi.org/10.1002/cam4.4426

Trends Cancer. 2021 Nov 11. pii: S2405-8033(21)00210-7. [Epub ahead of print]

Cancer catecholamine conundrum.

H Wackerhage, J F Christensen, M Ilmer, I von Luettichau, B W Renz, M Schönfelder.

Exercise, psychosocial stress, and drugs such as adrenergic agonists and antagonists increase the concentrations of catecholamines and/or alter adrenergic signaling. Intriguingly, exercise studies universally suggest that catecholamines are cancer-inhibiting whereas cancer stress studies typically report the opposite, whereas β-blocker studies show variable effects. Here, we term variable effects of catecholamines in cancer the cancer catecholamine conundrum. Variable effects of catecholamines can potentially be explained by variable expression of nine adrenergic receptor isoforms and by other factors including catecholamine effects on cancer versus immune or endothelial cells. Future studies on catecholamines and cancer should seek to understand the mechanisms that explain variable effects of catecholamines in cancer to utilize beneficial or block detrimental effects of catecholamines in cancer patients.

Keywords: adrenergic receptors; catecholamines; exercise; stress

DOI: https://doi.org/10.1016/j.trecan.2021.10.005