bims-netuvo 2022-05-22 papers

Nat Commun. 2022 May 19. 13(1): 2785

Neuronal hyperexcitability drives central and peripheral nervous system tumor progression in models of neurofibromatosis-1.

Corina Anastasaki, Juan Mo, Ji-Kang Chen, Jit Chatterjee, Yuan Pan, Suzanne M Scheaffer, Olivia Cobb, Michelle Monje, Lu Q Le, David H Gutmann.

Neuronal activity is emerging as a driver of central and peripheral nervous system cancers. Here, we examined neuronal physiology in mouse models of the tumor predisposition syndrome Neurofibromatosis-1 (NF1), with different propensities to develop nervous system cancers. We show that central and peripheral nervous system neurons from mice with tumor-causing Nf1 gene mutations exhibit hyperexcitability and increased secretion of activity-dependent tumor-promoting paracrine factors. We discovered a neurofibroma mitogen (COL1A2) produced by peripheral neurons in an activity-regulated manner, which increases NF1-deficient Schwann cell proliferation, establishing that neurofibromas are regulated by neuronal activity. In contrast, mice with the Arg1809Cys Nf1 mutation, found in NF1 patients lacking neurofibromas or optic gliomas, do not exhibit neuronal hyperexcitability or develop these NF1-associated tumors. The hyperexcitability of tumor-prone Nf1-mutant neurons results from reduced NF1-regulated hyperpolarization-activated cyclic nucleotide-gated (HCN) channel function, such that neuronal excitability, activity-regulated paracrine factor production, and tumor progression are attenuated by HCN channel activation. Collectively, these findings reveal that NF1 mutations act at the level of neurons to modify tumor predisposition by increasing neuronal excitability and activity-regulated paracrine factor production.

DOI: https://doi.org/10.1038/s41467-022-30466-6

Front Oncol. 2022 ;12 889862

Survival Impacts of Perineural Invasion on Patients Under Different Radical Hysterectomies Due to Early Cervical Cancer.

Wei-Wei Wei, Huihui Wang, Hong Zheng, Jiming Chen, Ru-Xia Shi.

Objective: Cervical cancer is a common gynecological malignancy. In addition to the open radical hysterectomy (ORH) and laparoscopic radical hysterectomy (LRH), laparoscopic nerve-sparing radical hysterectomy (LNSRH) could be another treatment option since it could preserve urinary, colorectal, and sexual functions. However, LNSRH might result in early cancer metastasis and recurrence due to inadequate tumor resection. Additionally, whether LNSRH should be considered based on perineural invasion (PNI) status remains controversial. To assess different types of hysterectomy on the outcome of early cervical cancer with PIN.
Methods: A retrospective study was performed in early cervical cancer patients who received ORH, LRH, or LNSRH between January 2012 and December 2019. Age, FIGO cancer stages, histopathological types, tumor size, histological grade, invasion depth, lymph node metastasis, lymphovascular space invasion, and PNI were documented. Disease-free survival (DFS) and overall survival (OS) were recorded.
Results: A total of 174 patients were included, with 33, 69, and 72 patients received LRH, ORH, and LNSRH, respectively. Twenty-one patients (12.1%) had PNI. DFS (P = 0.000) and OS (P = 0.022) periods were shortened in positive PNI patients than in negative PNI patients (P = 0.000 and 0.022, respectively). In patients with positive PNI, lymph node metastasis, but not the surgery type, was an independent risk factor for DFS and OS (P = 0.000).
Conclusion: Early cervical cancer patients with PNI had shorter postoperative DFS and OS periods. In these patients, lymph node metastasis, but not the type of hysterectomy, was independently associated with DFS and OS.

Keywords: cervical cancer; laparoscopic surgery; nerve-sparing radical hysterectomy; perineural invasion; survival impacts

DOI: https://doi.org/10.3389/fonc.2022.889862

Cancer Med. 2022 May 16.

Interleukin 6/gp130 axis promotes neural invasion in pancreatic cancer.

Hidetaka Suzuki, Shuichi Mitsunaga, Masafumi Ikeda, Takao Aoyama, Kazumi Yoshizawa, Masayuki Yamaguchi, Masami Suzuki, Minoru Narita, Toshikatsu Kawasaki, Atsushi Ochiai.

BACKGROUND: Nerve invasion (N-inv) is an important prognostic factor in pancreatic ductal adenocarcinoma (PDAC). Elucidation of circulating N-inv stimulators could provide deeper insights and novel perspectives for PDAC therapy. The interleukin (IL)-6/gp130 axis was evaluated in this study as a candidate N-inv stimulator.
METHODS: A human pancreatic cancer (PC) cell, Capan-1, was confirmed to have the stimulant activity of IL-6/gp130 axis through the evaluation of mRNA, cell surface protein and intracellular protein levels and chemotaxis and wound healing assay. The upregulation of IL-6/gp130 axis was evaluated using tumor-derived IL-6 level and intratumoral pSTAT3 expression in N-inv of murine sciatic nerves by intraneural injection of Capan-1 cell (N-inv model) and using resected pancreatic cancer tissue and clinical data from 46 PDAC patients.
RESULTS: mRNA and protein expressions of IL-6 and IL-6 receptor were found in whole cell lysate and condition medium from PC cell. Cell surface protein expression of gp130 were clearly detected on PC cell. IL-6 promoted migration and chemotaxis of PC cell. Serum IL-6 and tumoral IL-6 mRNA levels in N-inv model mice were significantly higher than those in subcutaneous tumor mice (p = 0.004 and p = 0.002, respectively). Silencing of IL-6 and gp130 on PC cell and administration of an anti-IL-6 receptor antibody, tocilizumab, suppressed N-inv, compared to each control (p = 0.070, p = 0.118 and p = 0.122, respectively). In PDAC patients, the high-N-inv group showed poor prognosis (p =0.059) and elevated serum levels of IL-6 and C-reactive protein, synthesis of which is promoted by IL-6, compared to those in the low-N-inv group (p = 0.006 and p = 0.075, respectively). Tumoral gp130 expression at N-inv was higher than that in the primary pancreatic tumor (p = 0.026).
CONCLUSION: Biological activity of IL-6/gp130 axis promoted N-inv in murine model and was upregulated in PDAC patients with severe N-inv. This study is the first evidence that the IL-6/gp130 axis offers a potential therapeutic target in PDAC with N-inv.

Keywords: mouse models; pancreatic cancer; pancreatic ductal adenocarcinoma; translational research

DOI: https://doi.org/10.1002/cam4.4823

Breast Cancer Res. 2022 May 14. 24(1): 33

Beta 2 adrenergic receptor and mu opioid receptor interact to potentiate the aggressiveness of human breast cancer cell by activating the glycogen synthase kinase 3 signaling.

Bénédicte Rousseau, Sengottuvelan Murugan, Ajay Palagani, Dipak K Sarkar.

BACKGROUND: Opioid and beta-adrenergic receptors are recently shown to cross talk via formation of receptor heterodimers to control the growth and proliferation of breast cancer cells. However, the underlying cell signaling mechanism remained unclear.
METHODS: To determine the effect of the interaction of the two systems in breast cancer, we employed triple-negative breast cancer cell lines MDA-MB-231 and MDA-MB-468, CRISPR or chemical inhibition or activation of beta-adrenergic receptors (B2AR) and mu-opioid receptors (MOR) gene, and PCR array technology and studied aggressive tumor phenotype and signaling cascades.
RESULTS: We show here that in triple-negative breast cancer cells, the reduction in expression B2AR and MOR by genetic and pharmacological tools leads to a less aggressive phenotype of triple-negative breast cancer cells in vitro and in animal xenografts. Genomic analysis indicates the glycogen synthase kinase 3 (GSK3) pathway as a possible candidate messenger system involved in B2AR and MOR cross talk. GSK3 inactivation in MDA-MB-231 and MDA-MB-468 cells induced similar phenotypic changes as the inhibition of B2AR and/or MOR, while a GSK3 activation by wortmannin reversed the effects of B2AR and/or MOR knockdown on these cells. GSK3 inactivation also prevents B2AR agonist norepinephrine or MOR agonist DAMGO from affecting MDA-MB-231 and MDA-MB-468 cell proliferation.
CONCLUSIONS: These data confirm a role of B2AR and MOR interaction in the control of breast cancer cell growth and identify a possible role of the GSK3 signaling system in mediation of these two receptors' cross talk. Screening for ligands targeting B2AR and MOR interaction and/or the GSK3 system may help to identify novel drugs for the prevention of triple-negative breast cancer cell growth and metastasis.

Keywords: Beta-adrenergic receptor; GSK3 signaling; Gene knockdown; Growth and metastasis; Mu-opioid receptor; Pharmacological agents; Triple-negative breast cancer

DOI: https://doi.org/10.1186/s13058-022-01526-y

Integr Cancer Ther. 2022 Jan-Dec;21:21 15347354221096081

Biobehavioral Pathways and Cancer Progression: Insights for Improving Well-Being and Cancer Outcomes.

Aeson Chang, Erica K Sloan, Michael H Antoni, Jennifer M Knight, Rachel Telles, Susan K Lutgendorf.

The relationship between psychosocial factors and cancer has intrigued people for centuries. In the last several decades there has been an expansion of mechanistic research that has revealed insights regarding how stress activates neuroendocrine stress-response systems to impact cancer progression. Here, we review emerging mechanistic findings on key pathways implicated in the effect of stress on cancer progression, including the cellular immune response, inflammation, angiogenesis, and metastasis, with a primary focus on the mediating role of the sympathetic nervous system. We discuss converging findings from preclinical and clinical cancer research that describe these pathways and research that reveals how these stress pathways may be targeted via pharmacological and mind-body based interventions. While further research is required, the body of work reviewed here highlights the need for and feasibility of an integrated approach to target stress pathways in cancer patients to achieve comprehensive cancer treatment.

Keywords: beta-adrenergic; biobehavioral; cancer progression; cortisol; inflammation; mind-body interventions; stress; sympathetic nervous system

DOI: https://doi.org/10.1177/15347354221096081