bims-netuvo 2022-10-16 papers

Cancers (Basel). 2022 Oct 01. pii: 4817. [Epub ahead of print]14(19):

Nerve Density and Neuronal Biomarkers in Cancer.

Shahrukh R Ali, Madeleine Jordan, Priyadharsini Nagarajan, Moran Amit.

Certain histologic characteristics of neurons, novel neuronal biomarkers, and nerve density are emerging as important diagnostic and prognostic tools in several cancers. The tumor microenvironment has long been known to promote tumor development via promoting angiogenesis and cellular proliferation, but new evidence has shown that neural proliferation and invasion in the tumor microenvironment may also enable tumor growth. Specific neuronal components in peripheral nerves and their localization in certain tumor sites have been identified and associated with tumor aggressiveness. In addition, dense neural innervation has been shown to promote tumorigenesis. In this review, we will summarize the histological components of a nerve, explore the neuronal biomarkers found in tumor sites, and discuss clinical correlates between tumor neurobiology and patient prognosis.

Keywords: cancer; neoplasms; nerve density; nerve pathology; nerve tissue; nerves; neural factors; tumor microenvironment

DOI: https://doi.org/10.3390/cancers14194817

Int J Mol Sci. 2022 Sep 29. pii: 11495. [Epub ahead of print]23(19):

Gut-Brain Axis: Insights from Hippocampal Neurogenesis and Brain Tumor Development in a Mouse Model of Experimental Colitis Induced by Dextran Sodium Sulfate.

Roberta Vitali, Clara Prioreschi, Laura Lorenzo Rebenaque, Eleonora Colantoni, Daniela Giovannini, Sarah Frusciante, Gianfranco Diretto, Francisco Marco-Jiménez, Mariateresa Mancuso, Arianna Casciati, Simonetta Pazzaglia.

Chronic inflammatory bowel disorders (IBD) are idiopathic diseases associated with altered intestinal permeability, which in turn causes an exaggerated immune response to enteric antigens in a genetically susceptible host. A rise in psych cognitive disorders, such as anxiety and depression, has been observed in IBD patients. We here report investigations on a model of chemically induced experimental colitis by oral administration of sodium dextran sulfate (DSS) in C57BL/6 mice. We investigate, in vivo, the crosstalk between the intestine and the brain, evaluating the consequences of intestinal inflammation on neuroinflammation and hippocampal adult neurogenesis. By using different DSS administration strategies, we are able to induce acute or chronic colitis, simulating clinical characteristics observed in IBD patients. Body weight loss, colon shortening, alterations of the intestinal mucosa and fecal metabolic changes in amino acids-, lipid- and thiamine-related pathways are observed in colitis. The activation of inflammatory processes in the colon is confirmed by macrophage infiltration and increased expression of the proinflammatory cytokine and oxidative stress marker (Il-6 and iNOS). Interestingly, in the hippocampus of acutely DSS-treated mice, we report the upregulation of inflammatory-related genes (Il-6, Il-1β, S-100, Tgf-β and Smad-3), together with microgliosis. Chronic DSS treatment also resulted in neuroinflammation in the hippocampus, indicated by astrocyte activation. Evaluation of stage-specific neurogenesis markers reveals deficits in the dentate gyrus after acute and chronic DSS treatments, indicative of defective adult hippocampal neurogenesis. Finally, based on a possible causal relationship between gut-related inflammation and brain cancer, we investigate the impact of DSS-induced colitis on oncogenesis, using the Ptch1+/-/C57BL/6 mice, a well-established medulloblastoma (MB) mouse model, finding no differences in MB development between untreated and DSS-treated mice. In conclusion, in our experimental model, the intestinal inflammation associated with acute and chronic colitis markedly influences brain homeostasis, impairing hippocampal neurogenesis but not MB oncogenesis.

Keywords: DSS-induced colitis; adult hippocampal neurogenesis; brain; medulloblastoma; metabolomics; neuroinflammation

DOI: https://doi.org/10.3390/ijms231911495

Front Oncol. 2022 ;12 951437

Reclassification of endometrial cancer and identification of key genes based on neural-related genes.

Fan Chen, Tiansheng Qin, Yigan Zhang, Linzhen Wei, Yamei Dang, Peixia Liu, Weilin Jin.

Endometrial cancer (EC) is the most common gynecologic malignancy, and its incidence has been increasing every year. Nerve signaling is part of the tumor microenvironment and plays an active role in tumor progression and invasion. However, the relationship between the expression of neural-related genes (NRGs) and prognosis in endometrial cancer remains unknown. In this study, we obtained RNA sequencing data of EC from The Cancer Genome Atlas (TCGA). Endometrial cancer was classified into two subtypes based on the expression of neural-associated genes (NRGs), with statistical differences in clinical stage, pathological grading, and prognosis. A prognostic prediction model was established by LASSO-Cox analysis, and the results showed that high expression of NRGs was associated with poor survival prognosis. Further, CHRM2, GRIN1, L1CAM, and SEMA4F were found to be significantly associated with clinical stage, immune infiltration, immune response, and important signaling pathways in endometrial cancer. The reclassification of endometrial cancer based on NRG expression would be beneficial for future clinical practice. The genes CHRM2, GRIN1, L1CAM, and SEMA4F might serve as potential biomarkers of EC prognosis.

Keywords: Endometrial cancer; biomarker; immune infiltration; nerve-cancer crosstalk; neural-related genes (NRGs)

DOI: https://doi.org/10.3389/fonc.2022.951437

Int J Mol Sci. 2022 Oct 05. pii: 11835. [Epub ahead of print]23(19):

Adenosine, Schizophrenia and Cancer: Does the Purinergic System Offer a Pathway to Treatment?

Abdul-Rizaq Hamoud, Karen Bach, Ojal Kakrecha, Nicholas Henkel, Xiaojun Wu, Robert E McCullumsmith, Sinead M O'Donovan.

For over a century, a complex relationship between schizophrenia diagnosis and development of many cancers has been observed. Findings from epidemiological studies are mixed, with reports of increased, reduced, or no difference in cancer incidence in schizophrenia patients. However, as risk factors for cancer, including elevated smoking rates and substance abuse, are commonly associated with this patient population, it is surprising that cancer incidence is not higher. Various factors may account for the proposed reduction in cancer incidence rates including pathophysiological changes associated with disease. Perturbations of the adenosine system are hypothesized to contribute to the neurobiology of schizophrenia. Conversely, hyperfunction of the adenosine system is found in the tumor microenvironment in cancer and targeting the adenosine system therapeutically is a promising area of research in this disease. We outline the current biochemical and pharmacological evidence for hypofunction of the adenosine system in schizophrenia, and the role of increased adenosine metabolism in the tumor microenvironment. In the context of the relatively limited literature on this patient population, we discuss whether hypofunction of this system in schizophrenia, may counteract the immunosuppressive role of adenosine in the tumor microenvironment. We also highlight the importance of studies examining the adenosine system in this subset of patients for the potential insight they may offer into these complex disorders.

Keywords: adenosine; cancer; epidemiology; purinergic signaling; schizophrenia

DOI: https://doi.org/10.3390/ijms231911835

Biomaterials. 2022 Oct 05. pii: S0142-9612(22)00463-X. [Epub ahead of print]290 121823

Human cancer cells generate spontaneous calcium transients and intercellular waves that modulate tumor growth.

Chenyu Liang, Qian Zhang, Xin Chen, Jiawei Liu, Mai Tanaka, Shu Wang, Sharon E Lepler, Zeyuan Jin, Dietmar W Siemann, Bo Zeng, Xin Tang.

Electrically excitable cells such as neurons transmit long-distance calcium or electrical signals to regulate their physiological functions. While the molecular underpinnings and down-stream effects of these intercellular communications in excitable cells have been well appreciated, little is known about whether and how non-excitable cancer cells spontaneously initiate and transmit long-distance intercellular signals. Here we report that non-excitable human colon and prostate cancer cells spontaneously initiate and spread intercellular calcium waves, in vitro and ex vivo. Xenograft model studies suggest that these calcium signals promote the growth rate of tumors in mice. Pharmacological studies elucidated that the inositol-trisphosphate-receptor (IP3R)-regulated calcium release from endoplasmic reticulum (ER), which is activated by the Gq-PLC-IP3R pathway, is a major cause for the initiation of spontaneous calcium transients. Further, the spatial-temporal characteristics of calcium dynamics can be tuned by the culture substrates of different mechanical stiffnesses. Our results provide evidence that calcium dynamics enables long-distance functional communication in non-excitable cancer cells and offer the potential to modulate calcium signaling for new cancer therapies.

Keywords: Electrophysiology; Fluorescent calcium imaging; G(q)-PLC-IP(3)R pathway; Human colon cancer; Long-distance signal transmission; Mechanical microenvironment; Pharmacology; Spontaneous intra- and inter-cellular calcium signals; Tumor growth; Xenograft model

DOI: https://doi.org/10.1016/j.biomaterials.2022.121823

Histopathology. 2022 Oct 10.

Prognosis of mucinous colon cancer is determined by histological biomarkers rather than microsatellite instability.

Peter H van Zwam, Elisa M Vink-Börger, Carolien M Bronkhorst, Adriaan P de Bruine, Anneke A van der Wurff, Harm J T Rutten, Valery E P P Lemmens, Iris D Nagtegaal, Niek Hugen.

BACKGROUND: The prognostic value of microsatellite instability (MSI) as well as other histological characteristics as lymphovascular invasion (LI), perineural invasion (PNI) and extramural vascular invasion (EMVI) is unclear in colorectal mucinous carcinoma (MC). This study aims to determine the relevance of these factors in MC patients and analyzes the role of MSI in stage III MC patients treated with adjuvant chemotherapy.
PATIENTS AND METHODS: A cohort of 650 patients diagnosed with stage I-IV colonic MC from 2000 to 2010 was selected from PALGA, the nationwide Dutch pathology databank. Histopathology was revised and MMR status determined. Univariate and multivariate survival analyses were performed.
RESULTS: dMMR was found in 33% of MCs and correlated with female gender and right-sidedness, but also with lower tumor stage (stage I/II: 73.2% versus 47%; p<0.0001) and the absence of EMVI (9.7% versus 23.7%; p<0.0001) and PNI (5.6% versus 12.7%; p=0.005). On univariate analysis OS was better for dMMR MC than for pMMR MC (median OS of 9.7 years versus 5.0 years; p=0.009), but MMR status was no longer a relevant prognostic factor on multivariate analysis (HR 0.91, 95% confidence interval 0.70-1.18). Stage III MC patients benefitted from adjuvant chemotherapy, and dMMR status was associated with better OS in this group (HR 0.35, 95% confidence interval 0.13-0.94).
CONCLUSION: EMVI, LI and PNI, but not MMR status are independent prognostic factors for survival in MC patients. Stage III MC patients benefit from adjuvant chemotherapy and dMMR status is associated with improved survival when adjuvant chemotherapy is given.

Keywords: adjuvant chemotherapy; colon cancer; microsatellite instability; mismatch repair deficiency; mucinous carcinoma

DOI: https://doi.org/10.1111/his.14818