bims-netuvo Biomed News
on Nerves in tumours of visceral organs
Issue of 2022‒01‒16
twelve papers selected by
Maksym V. Kopanitsa
The Francis Crick Institute

  1. FASEB Bioadv. 2022 Jan;4(1): 29-42
      The identification of nerves in the tumor microenvironment has ushered in a new area of research in cancer biology. Numerous studies demonstrate the presence of various types of peripheral nerves (sympathetic, parasympathetic, sensory) within the tumor microenvironment; moreover, an increased density of nerves in the tumor microenvironment correlates with worse prognosis. In this review, we address the current understanding of nerve-mediated alterations of the tumor microenvironment and how they impact disease through a variety of processes, including direct nerve-cancer cell communication, alteration of the infiltrative immune population, and alteration of stromal components.
    Keywords:  cancer; immune escape; neuro‐immune communication; tumor innervation; tumor microenvironment
  2. Life Sci. 2022 Jan 10. pii: S0024-3205(22)00005-4. [Epub ahead of print]291 120305
      BACKGROUND: Inactivation of sensory neurons expressing transient receptor potential vanilloid 1 (TRPV1) enhances breast cancer metastasis. Sensory neurons have profound effects on immune response to a wide range of diseases including cancer. Hence, activation of sensory nerves using feasible approaches such as specific TRPV1 agonists may inhibit breast cancer metastasis through neuroimmune pathways. TRPV1 agonists are considered for the treatment of pain and inflammatory diseases.METHODS: We here first determined the effects of four different TRPV1 agonists on proliferation of three different metastatic breast carcinoma cells since TRPV1 is also expressed in cancer cells. Based on the results obtained under in-vitro conditions, brain metastatic breast carcinoma cells (4TBM) implanted orthotopically into the mammary-pad of Balb-c mice followed by olvanil treatment (i.p.). Changes in tumor growth, metastasis and immune response to cancer cells were determined.
    RESULTS: Olvanil dose-dependently activated sensory nerve fibers and markedly suppressed lung and liver metastasis without altering the growth of primary tumors. Olvanil (5 mg/kg) systemically increased T cell count, enhanced intra-tumoral recruitment of CD8+ T cells and increased IFN-γ response to irradiated cancer cells and Con-A. Anti-inflammatory changes such as increased IL-10 and decrease IL-6 as well as S100A8+ cells were observed following olvanil treatment.
    CONCLUSIONS: Our results show that anti-metastatic effects of olvanil is mainly due to activation of neuro-immune pathways since olvanil dose used here is not high enough to directly activate immune cells. Furthermore, olvanil effectively depletes sensory neuropeptides; hence, olvanil is a good non-pungent alternative to capsaicin.
    Keywords:  Immune cells; Liver metastasis; Lung metastasis; Metastatic breast cancer; Microenvironment; Olvanil; TRPV1
  3. Toxicol Appl Pharmacol. 2022 Jan 05. pii: S0041-008X(22)00002-3. [Epub ahead of print]436 115863
      Solid tumors are commonly treated with cisplatin, which can cause off-target side effects in cancer patients. Chronotherapy is a potential strategy to reduce drug toxicity. To determine the effectiveness of timed-cisplatin treatment in mammals, we compared two conditions: clock disrupted jet-lag and control conditions. Under normal and disrupted clock conditions, triple-negative mammary carcinoma cells were injected subcutaneously into eight-week-old NOD.Cg-Prkdcscid/J female mice. Tumor volumes and body weights were measured in these mice before and after treatment with cisplatin. We observed an increase in tumor volumes in mice housed under disrupted clock compared to the normal clock conditions. After treatment with cisplatin, we observed a reduced tumor growth rate in mice treated at ZT10 compared to ZT22 and untreated cohorts under normal clock conditions. However, these changes were not seen with the jet-lag protocol. We also observed greater body weight loss in mice treated with ZT10 compared to ZT22 or untreated mice in the jet-lag protocol. Our observations suggest that the effectiveness of cisplatin in mammary carcinoma treatment is time-dependent in the presence of the circadian clock.
    Keywords:  Breast cancer; Chronotherapy; Cisplatin; Clock disruption
  4. FASEB Bioadv. 2022 Jan;4(1): 76-89
      Tumor innervation has recently been documented and characterized in various settings and tumor types. However, the role that nerves innervating tumors play in the pathogenesis of cancer has not been clarified. In this study, we searched for neural signaling from bulk RNA sequencing from The Cancer Genome Atlas (TCGA) dataset and looked for patterns of interactions between different cell types within the tumor environment. Using a presynapse signature (PSS) as a probe, we showed that multiple stromal cell types crosstalk and/or contribute to neural signals. Based on the correlation and linear regression, we hypothesized that neural signals contribute to an immune-suppressive tumor microenvironment (TME). To test this hypothesis, we performed in vitro dorsal root ganglion (DRG)/macrophage coculture experiments. Compared to the M2 macrophage monoculture, the DRG/M2 macrophage coculture prevented anti-inflammatory M2 to pro-inflammatory M1 polarization by LPS stimulation. Finally, a survey of different TCGA tumor types indicated that higher RNA neural signature is predictive of poor patient outcomes in multiple tumor types.
    Keywords:  TME, tumor‐innervating nerves; immune suppressive; neural signal; presynapse signature; tumor microenvironment
  5. Cancers (Basel). 2021 Dec 28. pii: 124. [Epub ahead of print]14(1):
      The aims of this study were to assess the prevalence of perineural invasion (PNI) in vulvar squamous cell carcinoma (VSCC) and its prognostic role in locoregional recurrence (LRR) and cancer-specific survival (CSS). We performed a retrospective analysis of 223 consecutive stage IB-IIIC surgically treated VSCCs at S. Anna Hospital, University of Turin, from 2000 to 2019. We identified 133/223 (59.6%) patients with PNI-positive VSCCs. PNI was associated with aggressive biological features (i.e., advanced FIGO stage, larger tumor diameter, greater depth of invasion, a higher number of metastatic lymph nodes, and lymphovascular invasion) and shorter 5-year CSS (78% vs. 90%, log-rank p = 0.02) compared with PNI-negative VSCCs. Multivariate analysis showed that PNI (HR 2.99 CI 95% 1.17-7.63; p = 0.02) and the presence of tumor cells on pathological surgical margins (HR 3.13 CI 95% 1.37-7.13; p = 0.007) are independent prognostic factors for CSS. PNI does not appear to be related to LRR, but is an independent prognostic factor for worse survival outcomes. Future studies are necessary to explore the possible value of PNI in tailoring the choice of adjuvant treatment.
    Keywords:  perineural invasion; prognostic factors; recurrence; survival; vulvar cancer; vulvar squamous-cell carcinoma
  6. Pathol Int. 2022 Jan 10.
      Perineural invasion (PNI) is known as a poor prognostic factor in colorectal cancer (CRC). Although histopathological evaluation of PNI is usually conducted on hematoxylin and eosin (HE)-stained sections (HE-PNI), it remains controversial whether PNI can be precisely evaluated only by HE-staining, and its concise mechanisms causing worse prognosis remains elusive. In this study, we examined the impact of PNI evaluated by S-100-immunostaining (S100-PNI) on postoperative mortality in 279 consecutive CRC patients and further investigated its association with the tumor immune microenvironment. S100-PNI was present in 67.3% of tumors whereas HE-PNI was present in 18.5%. A 5-year cumulative incidence of death in the S100-PNI-positive group was significantly higher than that in the S100-PNI-negative group. Further statistical analyses revealed that S100-PNI was an independent prognostic factor of all-cause mortality in stage I/II but not in stage III/IV. Importantly, S100-PNI was associated with the altered tumor immune microenvironment. Infiltrating immune cell profiling revealed that stromal lymphocytic reaction, which was inversely correlated with postoperative mortality, was significantly reduced in S100-PNI-positive tumors compared to S100-PNI-negative tumors in stage I/II. These results indicated that S100-PNI was a poor prognostic factor in stage I/II CRC with possible association with immunosuppression in the tumor.
    Keywords:  S-100; colorectal cancer; immunosuppression; perineural invasion (PNI); tumor immune microenvironment
  7. Front Oncol. 2021 ;11 774459
      Background: Perineural invasion (PNI) is associated with a poor prognosis for cervical cancer and influences surgical strategies. However, a preoperative evaluation that can determine PNI in cervical cancer patients is lacking.Methods: After 1:1 propensity score matching, 162 cervical cancer patients with PNI and 162 cervical cancer patients without PNI were included in the training set. Forty-nine eligible patients were enrolled in the validation set. The PNI-positive and PNI-negative groups were compared. Multivariate logistic regression was performed to build the PNI prediction nomogram.
    Results: Age [odds ratio (OR), 1.028; 95% confidence interval (CI), 0.999-1.058], adenocarcinoma (OR, 1.169; 95% CI, 0.675-2.028), tumor size (OR, 1.216; 95% CI, 0.927-1.607), neoadjuvant chemotherapy (OR, 0.544; 95% CI, 0.269-1.083), lymph node enlargement (OR, 1.953; 95% CI, 1.086-3.550), deep stromal invasion (OR, 1.639; 95% CI, 0.977-2.742), and full-layer invasion (OR, 5.119; 95% CI, 2.788-9.799) were integrated in the PNI prediction nomogram based on multivariate logistic regression. The PNI prediction nomogram exhibited satisfactory performance, with areas under the curve of 0.763 (95% CI, 0.712-0.815) for the training set and 0.860 (95% CI, 0.758-0.961) for the validation set. Moreover, after reviewing the pathological slides of patients in the validation set, four patients initially diagnosed as PNI-negative were recognized as PNI-positive. All these four patients with false-negative PNI were correctly predicted to be PNI-positive (predicted p > 0.5) by the nomogram, which improved the PNI detection rate.
    Conclusion: The nomogram has potential to assist clinicians when evaluating the PNI status, reduce misdiagnosis, and optimize surgical strategies for patients with cervical cancer.
    Keywords:  biomarker; cervical cancer; nomogram; perineural invasion; predictive model
  8. Arch Pathol Lab Med. 2022 Jan 13.
      CONTEXT.—: Perineural invasion (PNI) by prostate cancer has been associated with adverse pathology, including extraprostatic extension. However, the significance of PNI quantification on prostate biopsy (PBx) remains unclear.OBJECTIVE.—: To compare radical prostatectomy (RP) findings and long-term outcomes in patients whose PBx had exhibited PNI.
    DESIGN.—: We assessed 497 consecutive patients undergoing sextant (6-site/≥12-core) PBx showing conventional adenocarcinoma followed by RP.
    RESULTS.—: PNI was found in 1 (n = 290)/2 (n = 132)/3 (n = 47)/4 (n = 19)/5 (n = 5)/6 (n = 4) of the sites/regions of PBx. Compared with a single PNI site, multiple PNIs were significantly associated with higher preoperative prostate-specific antigen, higher Grade Group (GG) on PBx or RP, higher pT or pN category, positive surgical margin, and larger estimated tumor volume. When compared in subgroups of patients based on PBx GG, significant differences in RP GG (GG1-3), pT (GG1-2/GG1-3/GG2/GG3), surgical margin status (GG1-3/GG3/GG5), or tumor volume (GG1-2/GG1-3/GG2/GG3) between 1 versus multiple PNIs were observed. Moreover, there were significant differences in prostate-specific antigen (PNI sites: 1-2 versus 3-6/1-3 versus 4-6/1-4 versus 5-6), RP GG (1-3 versus 4-6/1-4 versus 5-6), pT (1-2 versus 3-6/1-3 versus 4-6), pN (1-3 versus 4-6), or tumor volume (1-2 versus 3-6/1-4 versus 5-6). Outcome analysis revealed significantly higher risks of disease progression in the entire cohort or PBx GG1-2/GG1-3/GG2/GG3/GG5 cases showing 2 to 6 PNIs, compared with respective controls with 1-site PNI. In multivariate analysis, multisite PNI was an independent predictor for progression (hazard ratio = 1.556, P = .03).
    CONCLUSIONS.—: Multiple sites of PNI on PBx were associated with worse histopathologic features in RP specimens and poorer prognosis. PNI may thus need to be specified, if present, in every sextant site on PBx, especially those showing GG1-3 cancer.
  9. Ann Hepatobiliary Pancreat Surg. 2022 Jan 11.
      Backgrounds/Aims: Pancreaticoduodenectomy (PD) is a standard surgical procedure for patients with periampullary cancer. During the follow-up period after PD, recurrence can be observed in various places with different prognosis. The aim of this study was to clarify the pattern of recurrence and factors affecting the survival of patients with periampullary cancer.Methods: Overall, 88 patients who received PD for distal common bile duct cancer or ampulla of Vater cancer were finally included and their clinical characteristics were analyzed. Patients were divided into three groups: recurrence-free (RF) group, an isolated locoregional recurrence (LR) group, and a distant metastasis (DM) group. Prognostic factors affecting recurrence in each group were analyzed and a survival analysis was performed.
    Results: Perineural invasion (PNI), T stage, and lymphovascular invasion (LVI) were significant risk factors for LR and PNI, lymph node metastasis, LVI, and T stage were associated with DM group compared to RF group in univariate analysis, respectively. N stage and PNI were significant risk factors (p = 0.046, p = 0.041) in overall survival of the LR and the DM groups. There was no significant difference in 5-year overall survival between the LR and DM groups.
    Conclusions: T stage was a significant risk factor of LR, while PNI was a significant risk factor of DM. There was no significant difference in overall survival depending on the site of recurrence.
    Keywords:  Bile duct cancer; Metastasis; Pancreaticoduodenectomy; Recurrence
  10. Front Oncol. 2021 ;11 792290
      Opioids are administered to cancer patients in the period surrounding tumour excision, and in the management of cancer-associated pain. The effects of opioids on tumour growth and metastasis, and their consequences on disease outcome, continue to be the object of polarised, discrepant literature. It is becoming clear that opioids contribute a range of direct and indirect effects to the biology of solid tumours, to the anticancer immune response, inflammation, angiogenesis and importantly, to the tumour-promoting effects of pain. A common misconception in the literature is that the effect of opioid agonists equates the effect of the mu-opioid receptor, the major target of the analgesic effect of this class of drugs. We review the evidence on opioid receptor expression in cancer, opioid receptor polymorphisms and cancer outcome, the effect of opioid antagonists, especially the peripheral antagonist methylnaltrexone, and lastly, the evidence available of a role for opioids through non-opioid receptor mediated actions.
    Keywords:  OGFr; TLR4; cancer; metastasis; opioid antagonist; opioid receptor
  11. ACS Appl Bio Mater. 2020 Sep 21. 3(9): 5796-5812
      Fascicular rearrangement of an injured peripheral nerve requires reconnection of nerve sprouts from anterior and Büngner bands from distal sides of the lesion, failing to which leads to inefficient regeneration of the injured nerve. However, existing neural scaffolds have limited neuroregeneration efficiency because of either the lack of alignment of fibers and a conductive second phase, leading to compromised electrical conductivity, or the lack of extracellular matrix components and in vivo validation. The present study reports a biocompatible, multiwall carbon nanotube (MWCNT)-reinforced, anisotropically conductive, electrospun, aligned nanofibrous scaffold, ensuring maximal peripheral nerve regeneration. Electrospinning parameters were modulated to deposit random and parallel fibers in separate scaffolds for comparative analysis on the effect of fiber alignment on regeneration. Both types of scaffolds were reinforced with MWCNTs to impart electrical conductivity. Nonreinforced scaffolds were nonconductive. In this comparative study, MWCNT-reinforced, aligned scaffolds showed better tensile property with increased conductivity along the direction of alignment, thereby ensuring an escalated neural-regeneration rate. Collectively, in vitro studies established the scaffolds to be highly biocompatible, promoting cell growth and proliferation. With 85% more anisotropic conductivity in the direction of the alignment and the degradation kinetics tuned to the regeneration regime, the MWCNT-reinforced, aligned scaffold efficiently healed injured sciatic nerves in rats within 30 days. Rigorous revivification of the tissue was due to coordinated Wallerian degeneration and expedited guided axonal regeneration. Structural and functional analysis of nerves in vivo showed the aligned, MWCNT-reinforced scaffold to be very efficient in peripheral sciatic nerve regeneration. This study notes the efficacy of the coaxially aligned, MWCNT-reinforced neural scaffold, with a capability of establishing remarkable advancement in the field of peripheral neural regeneration.
    Keywords:  MWCNT; anisotropic electrical conduction; neural scaffold; peripheral nerve injury regeneration; sciatic nerve
  12. J Vis Exp. 2021 Dec 23.
      Axonal transport maintains neuronal homeostasis by enabling the bidirectional trafficking of diverse organelles and cargoes. Disruptions in axonal transport have devastating consequences for individual neurons and their networks, and contribute to a plethora of neurological disorders. As many of these conditions involve both cell autonomous and non-autonomous mechanisms, and often display a spectrum of pathology across neuronal subtypes, methods to accurately identify and analyze neuronal subsets are imperative. This paper details protocols to assess in vivo axonal transport of signaling endosomes and mitochondria in sciatic nerves of anesthetized mice. Stepwise instructions are provided to 1) distinguish motor from sensory neurons in vivo, in situ, and ex vivo by using mice that selectively express fluorescent proteins within cholinergic motor neurons; and 2) separately or concurrently assess in vivo axonal transport of signaling endosomes and mitochondria. These complementary intravital approaches facilitate the simultaneous imaging of different cargoes in distinct peripheral nerve axons to quantitatively monitor axonal transport in health and disease.