bims-netuvo 2022-04-24 papers

Cell Death Dis. 2022 Apr 21. 13(4): 387

HGF/c-Met pathway facilitates the perineural invasion of pancreatic cancer by activating the mTOR/NGF axis.

Tao Qin, Ying Xiao, Weikun Qian, Xueni Wang, Mengyuan Gong, Qiqi Wang, Rui An, Liang Han, Wanxing Duan, Qingyong Ma, Zheng Wang.

Perineural invasion (PNI) is a pathologic feature of pancreatic cancer and is associated with poor outcomes, metastasis, and recurrence in pancreatic cancer patients. However, the molecular mechanism of PNI remains unclear. The present study aimed to investigate the mechanism that HGF/c-Met pathway facilitates the PNI of pancreatic cancer. In this study, we confirmed that c-Met expression was correlated with PNI in pancreatic cancer tissues. Activating the HGF/c-Met signaling pathway potentiated the expression of nerve growth factor (NGF) to recruit nerves and promote the PNI. Activating the HGF/c-Met signaling pathway also enhanced the migration and invasion ability of cancer cells to facilitate cancer cells invading nerves. Mechanistically, HGF/c-Met signaling pathway can active the mTOR/NGF axis to promote the PNI of pancreatic cancer. Additionally, we found that knocking down c-Met expression inhibited cancer cell migration along the nerve, reduced the damage of the sciatic nerve caused by cancer cells and protected the function of the sciatic nerve in vivo. Taken together, our findings suggest a supportive mechanism of the HGF/c-Met signaling pathway in promoting PNI by activating the mTOR/NGF axis in pancreatic cancer. Blocking the HGF/c-Met signaling pathway may be an effective target for the treatment of PNI.

DOI: https://doi.org/10.1038/s41419-022-04799-5

Cells. 2022 Apr 11. pii: 1294. [Epub ahead of print]11(8):

The Role of Extracellular Vesicles in Cancer-Nerve Crosstalk of the Peripheral Nervous System.

Yuanning Guo, Ziv Gil.

Although the pathogenic operations of cancer-nerve crosstalk (e.g., neuritogenesis, neoneurogensis, and perineural invasion-PNI) in the peripheral nervous system (PNS) during tumorigenesis, as well as the progression of all cancer types is continuing to emerge as an area of unique scientific interest and study, extensive, wide-ranging, and multidisciplinary investigations still remain fragmented and unsystematic. This is especially so in regard to the roles played by extracellular vesicles (EVs), which are lipid bilayer-enclosed nano- to microsized particles that carry multiple-function molecular cargos, facilitate intercellular communication in diverse processes. Accordingly, the biological significance of EVs has been greatly elevated in recent years, as there is strong evidence that they could contribute to important and possibly groundbreaking diagnostic and therapeutic innovations. This can be achieved and the pace of discoveries accelerated through cross-pollination from existing knowledge and studies regarding nervous system physiology and pathology, as well as thoroughgoing collaborations between oncologists, neurobiologists, pathologists, clinicians, and researchers. This article offers an overview of current and recent past investigations on the roles of EVs in cancer-nerve crosstalk, as well as in neural development, physiology, inflammation, injury, and regeneration in the PNS. By highlighting the mechanisms involved in physiological and noncancerous pathological cellular crosstalk, we provide hints that may inspire additional translational studies on cancer-nerve interplay.

Keywords: axonogenesis; cancer neuroscience; cancer–nerve crosstalk; exosome; innervation; microvesicle; neural influences in cancer (NIC); neurogenesis; peripheral nervous system (PNS); tumor microenvironment (TME)

DOI: https://doi.org/10.3390/cells11081294

Cancers (Basel). 2022 Apr 14. pii: 1979. [Epub ahead of print]14(8):

Tumor Innervation: History, Methodologies, and Significance.

James H Baraldi, German V Martyn, Galina V Shurin, Michael R Shurin.

The role of the nervous system in cancer development and progression has been under experimental and clinical investigation since nineteenth-century observations in solid tumor anatomy and histology. For the first half of the twentieth century, methodological limitations and opaque mechanistic concepts resulted in ambiguous evidence of tumor innervation. Differential spatial distribution of viable or disintegrated nerve tissue colocalized with neoplastic tissue led investigators to conclude that solid tumors either are or are not innervated. Subsequent work in electrophysiology, immunohistochemistry, pathway enrichment analysis, neuroimmunology, and neuroimmunooncology have bolstered the conclusion that solid tumors are innervated. Regulatory mechanisms for cancer-related neurogenesis, as well as specific operational definitions of perineural invasion and axonogenesis, have helped to explain the consensus observation of nerves at the periphery of the tumor signifying a functional role of nerves, neurons, neurites, and glia in tumor development.

Keywords: axonogenesis; cancer; neoneurogenesis; neurogenesis; neuroimmunology; neuroimmunooncology; tumor microenvironment

DOI: https://doi.org/10.3390/cancers14081979

Virchows Arch. 2022 Apr 21.

Detection of perineural invasion in prostate needle biopsies with deep neural networks.

Kimmo Kartasalo, Peter Ström, Pekka Ruusuvuori, Hemamali Samaratunga, Brett Delahunt, Toyonori Tsuzuki, Martin Eklund, Lars Egevad.

The presence of perineural invasion (PNI) by carcinoma in prostate biopsies has been shown to be associated with poor prognosis. The assessment and quantification of PNI are, however, labor intensive. To aid pathologists in this task, we developed an artificial intelligence (AI) algorithm based on deep neural networks. We collected, digitized, and pixel-wise annotated the PNI findings in each of the approximately 80,000 biopsy cores from the 7406 men who underwent biopsy in a screening trial between 2012 and 2014. In total, 485 biopsy cores showed PNI. We also digitized more than 10% (n = 8318) of the PNI negative biopsy cores. Digitized biopsies from a random selection of 80% of the men were used to build the AI algorithm, while 20% were used to evaluate its performance. For detecting PNI in prostate biopsy cores, the AI had an estimated area under the receiver operating characteristics curve of 0.98 (95% CI 0.97-0.99) based on 106 PNI positive cores and 1652 PNI negative cores in the independent test set. For a pre-specified operating point, this translates to sensitivity of 0.87 and specificity of 0.97. The corresponding positive and negative predictive values were 0.67 and 0.99, respectively. The concordance of the AI with pathologists, measured by mean pairwise Cohen's kappa (0.74), was comparable to inter-pathologist concordance (0.68 to 0.75). The proposed algorithm detects PNI in prostate biopsies with acceptable performance. This could aid pathologists by reducing the number of biopsies that need to be assessed for PNI and by highlighting regions of diagnostic interest.

Keywords: Artificial intelligence; Pathology; Perineural invasion; Prostate cancer

DOI: https://doi.org/10.1007/s00428-022-03326-3