bims-netuvo 2024-06-02 papers

Issue of 2024‒06‒02
seven papers selected by
Maksym V. Kopanitsa, The Francis Crick Institute

Biochim Biophys Acta Rev Cancer. 2024 May 23. pii: S0304-419X(24)00052-0. [Epub ahead of print]1879(4): 189121

Nerve-tumor crosstalk in tumor microenvironment: From tumor initiation and progression to clinical implications.

Zheng Zhang, Zhen Gang Lv, Miao Lu, Haifeng Li, Jiahua Zhou.

The autonomic nerve system (ANS) innervates organs and tissues throughout the body and maintains functional balance among various systems. Further investigations have shown that excessive activation of ANS not only causes disruption of homeostasis, but also may promote tumor formation. In addition, the dynamic interaction between nerve and tumor cells in the tumor microenvironment also regulate tumor progression. On the one hand, nerves are passively invaded by tumor cells, that is, perineural invasion (PNI). On the other hand, compared with normal tissues, tumor tissues are subject to more abundant innervation, and nerves can influence tumor progression through regulating tumor proliferation, metastasis and drug resistance. A large number of studies have shown that nerve-tumor crosstalk, including PNI and innervation, is closely related to the prognosis of patients, and contributes to the formation of cancer pain, which significantly deteriorates the quality of life for patients. These findings suggest that nerve-tumor crosstalk represents a potential target for anti-tumor therapies and the management of cancer pain in the future. In this review, we systematically describe the mechanism by which nerve-tumor crosstalk regulates tumorigenesis and progression.

Keywords: Crosstalk; Nerve; Tumor; Tumor microenvironment

DOI: https://doi.org/10.1016/j.bbcan.2024.189121

Cancer Lett. 2024 May 24. pii: S0304-3835(24)00380-X. [Epub ahead of print]594 216986

Crosstalk between the nervous system and tumor microenvironment: Functional aspects and potential therapeutic strategies.

Lei Wang, Jingjing Ge, Huiqiong Han, Yongxu Jia, Yanru Qin.

Recent advancements in understanding the tumor microenvironment (TME) have highlighted the critical role of the nervous system in cancer progression. This review comprehensively examines how the nervous system influences various aspects of tumorigenesis, including growth, motility, immune response, angiogenesis, and the behavior of cancer-associated fibroblasts (CAFs). We delineate the neurodevelopmental mechanisms associated with cancer, such as the secretion of neurotrophins and exosomes by cancer cells. Furthermore, we explore the emerging therapeutic strategy of targeting nerves associated with tumors. Evidence supporting this approach includes studies demonstrating direct tumor growth inhibition, enhanced efficacy of immunotherapy when combined with nervous system-modulating drugs, and the suppression of tumor blood vessel formation through nerve targeting. Finally, we discuss the current challenges in this field and emphasize the need for further exploration within cancer neuroscience.

Keywords: Angiogenesis; Immunity; Nervous system; Therapy; Tumor microenvironment

DOI: https://doi.org/10.1016/j.canlet.2024.216986

bioRxiv. 2024 May 14. pii: 2024.05.14.594163. [Epub ahead of print]

Immunotherapy-related cognitive impairment after CAR T cell therapy in mice.

Anna C Geraghty, Lehi Acosta-Alvarez, Maria Rotiroti, Selena Dutton, Michael R O'Dea, Pamelyn J Woo, Haojun Xu, Kiarash Shamardani, Rebecca Mancusi, Lijun Ni, Sara B Mulinyawe, Won Ju Kim, Shane A Liddelow, Robbie G Majzner, Michelle Monje.

Persistent central nervous system (CNS) immune dysregulation and consequent dysfunction of multiple neural cell types is central to the neurobiological underpinnings of a cognitive impairment syndrome that can occur following traditional cancer therapies or certain infections. Immunotherapies have revolutionized cancer care for many tumor types, but the potential long-term cognitive sequelae are incompletely understood. Here, we demonstrate in mouse models that chimeric antigen receptor (CAR) T cell therapy for both CNS and non-CNS cancers can impair cognitive function and induce a persistent CNS immune response characterized by white matter microglial reactivity and elevated cerebrospinal fluid (CSF) cytokines and chemokines. Consequently, oligodendroglial homeostasis and hippocampal neurogenesis are disrupted. Microglial depletion rescues oligodendroglial deficits and cognitive performance in a behavioral test of attention and short-term memory function. Taken together, these findings illustrate similar mechanisms underlying immunotherapy-related cognitive impairment (IRCI) and cognitive impairment following traditional cancer therapies and other immune challenges.

DOI: https://doi.org/10.1101/2024.05.14.594163

J Exp Clin Cancer Res. 2024 May 30. 43(1): 153

Placental growth factor promotes neural invasion and predicts disease prognosis in resectable pancreatic cancer.

Andreas Göhrig, Georg Hilfenhaus, Friederike Rosseck, Martina Welzel, Benjamin Moser, Gianluca Barbone, Catarina Alisa Kunze, Johannes Rein, Gregor Wilken, Michael Böhmig, Thomas Malinka, Frank Tacke, Marcus Bahra, Katharina M Detjen, Christian Fischer.

BACKGROUND: Surgery represents the only curative treatment option for pancreatic ductal adenocarcinoma (PDAC), but recurrence in more than 85% of patients limits the success of curative-intent tumor resection. Neural invasion (NI), particularly the spread of tumor cells along nerves into extratumoral regions of the pancreas, constitutes a well-recognized risk factor for recurrence. Hence, monitoring and therapeutic targeting of NI offer the potential to stratify recurrence risk and improve recurrence-free survival. Based on the evolutionary conserved dual function of axon and vessel guidance molecules, we hypothesize that the proangiogenic vessel guidance factor placental growth factor (PlGF) fosters NI. To test this hypothesis, we correlated PlGF with NI in PDAC patient samples and functionally assessed its role for the interaction of tumor cells with nerves.METHODS: Serum levels of PlGF and its soluble receptor sFlt1, and expression of PlGF mRNA transcripts in tumor tissues were determined by ELISA or qPCR in a retrospective discovery and a prospective validation cohort. Free circulating PlGF was calculated from the ratio PlGF/sFlt1. Incidence and extent of NI were quantified based on histomorphometric measurements and separately assessed for intratumoral and extratumoral nerves. PlGF function on reciprocal chemoattraction and directed neurite outgrowth was evaluated in co-cultures of PDAC cells with primary dorsal-root-ganglia neurons or Schwann cells using blocking anti-PlGF antibodies.
RESULTS: Elevated circulating levels of free PlGF correlated with NI and shorter overall survival in patients with PDAC qualifying for curative-intent surgery. Furthermore, high tissue PlGF mRNA transcript levels in patients undergoing curative-intent surgery correlated with a higher incidence and greater extent of NI spreading to tumor-distant extratumoral nerves. In turn, more abundant extratumoral NI predicted shorter disease-free and overall survival. Experimentally, PlGF facilitated directional and dynamic changes in neurite outgrowth of primary dorsal-root-ganglia neurons upon exposure to PDAC derived guidance and growth factors and supported mutual chemoattraction of tumor cells with neurons and Schwann cells.
CONCLUSION: Our translational results highlight PlGF as an axon guidance factor, which fosters neurite outgrowth and attracts tumor cells towards nerves. Hence, PlGF represents a promising circulating biomarker of NI and potential therapeutic target to improve the clinical outcome for patients with resectable PDAC.

Keywords: Axon guidance molecule; Cancer neuroscience; Nerves; Neural invasion; Pancreatic cancer; Placental growth factor (PlGF)

DOI: https://doi.org/10.1186/s13046-024-03066-z

Prostate. 2024 May 27.

Clinical and histopathological parameters in transrectal ultrasound-guided biopsies associated with tumor upgrading after radical prostatectomy: A comparative analysis of risk groups.

Mustafa Ozkaya, Muhammed Fatih Simsekoglu, Goktug Kalender, Kadir Can Sahin, Iclal Gurses.

BACKGROUND: Thanks to technological advances, prostate cancer (PCa) can be diagnosed at a younger age. It is known that most of these patients are in the low-intermediate risk group, and the histological grade of the tumor increases in half of those undergoing radical prostatectomy (Rp) compared to their diagnostic biopsies. This is especially important in terms of active surveillance (AS) and/or the timely evaluation of curative treatment options in patients diagnosed at an early age. Our aim was to investigate clinical and histopathological parameters that may be associated with an increase in the histological grade of the tumor in patients with acinar adenocarcinoma who were diagnosed by transrectal ultrasound-guided biopsy (TRUS-Bx) and underwent Rp.METHODS: A total of 205 patients with classical acinar adenocarcinoma diagnosed by TRUS-Bx without metastasis and who underwent Rp were grouped according to the D'Amico risk classification. Age at diagnosis, serum prostate-specific antigen (PSA), PSA density, prostate volume, Prostate Imaging Reporting and Data System (PI-RADS) score, clinical stage, Gleason Grade Group (GGG), high-grade intraepithelial neoplasia in tumor-free cores (HGPIN) (single and ≥2 cores), perineural invasion (PNI), and lymphovascular invasion (LVI) was obtained. Additionally, GGG, pathological stage, lymph node metastasis, surgical margin positivity, and tumor volume obtained from Rp were evaluated. Comparisons were made between the case groups in which the tumor grade increased and remained the same, in terms of age, serum PSA, PSA density, HGPIN in tumor-free cores (single and ≥2 cores), PNI, and LVI in all biopsies (with or without tumors), as well as risk groups. In addition, the relationships of HGPIN in tumor-free cores (single and ≥2 cores), PNI, and LVI on TRUS-Bx with age, serum PSA and PSA density, tumor volume, surgical margin positivity, pathological stage, lymph node metastasis, and risk groups were examined separately.
RESULTS: Of the patients, 72 (35.1%) were in the low-risk group, 95 (46.3%) in the intermediate-risk group, and 38 (18.5%) in the high-risk group. Most of the patients with an increased histological grade (n = 38, 48.1%) were in the low-risk group (p < 0.05) and had an advanced median age. HGPIN in single and ≥2 tumor-free cores and PNI were more common in these patients (p < 0.01, p < 0.001, and p < 0.05, respectively). According to the multivariable analysis, advanced age (odds ratio [OR]: 1.087, 95% confidence interval [CI]: 1.029-1.148, p < 0.05), high serum PSA (OR: 1.047, 95% CI: 1.006-1.090, p < 0.05), HGPIN in ≥2 tumor-free cores (OR: 6.346, 95% CI: 3.136-12.912, p < 0.001), and PNI (OR: 3.138, 95% CI: 1.179-8.356, p < 0.05) were independent risk factors for a tumor upgrade. Furthermore, being in the low-risk group was an independent risk factor when compared to the intermediate- and high-risk groups (OR: 0.187, 95% CI: 0.080-0.437, p < 0.001 and OR: 0.054, 95% CI: 0.013-0.230, p < 0.001, respectively). The HGPIN diagnosis was more common in the low- and intermediate-risk groups. Advanced age at diagnosis, high serum PSA and PSA density values were associated with PNI on TRUS-Bx. High serum PSA and PSA density values were associated with LVI on TRUS-Bx. Surgical margin positivity was higher in cases with PNI and LVI detected by TRUS-Bx. HGPIN in ≥2 tumor-free cores, PNI, and LVI on TRUS-Bx were associated with a higher rate of lymph node metastases.
CONCLUSIONS: In patients diagnosed with acinar adenocarcinoma, the presence of HGPIN even in a single tumor-free core on TRUS-Bx was found to be significant in terms of showing an increase in the histological tumor grade in Rp. The diagnosis of HGPIN in ≥2 tumor-free cores on TRUS-Bx was determined as an independent risk factor for an increased Gleason score after Rp. Furthermore, an advanced age, a high serum PSA value, being in the low-risk group, and the presence of PNI were associated with a tumor upgrade. HGPIN in ≥2 tumor-free cores, PNI, and LVI were also associated with lymph node metastasis. Therefore, the diagnosis of HGPIN should be signed out on pathological reports.

Keywords: HGPIN; adenocarcinoma; prostate biopsy; radical prostatectomy; tumor upgrading

DOI: https://doi.org/10.1002/pros.24751

J Neurosurg. 2024 May 31. 1-9

Robotic thoracic surgery for neurogenic tumors.

Benedikt Niedermaier, Raffaella Griffo, Matthias Grott, Henrike Deissner, Thomas Muley, Jan-Oliver Neumann, Hauke Winter, Martin Eichhorn.

OBJECTIVE: Thoracic neurogenic tumors usually present as benign nerve sheath tumors that can be resected via transthoracic or posterior approaches, depending on the anatomical location. Robot-assisted thoracic surgery (RATS) is increasingly being used for the transthoracic approach, but evidence is very limited. The authors initiated the current study to evaluate the efficacy and safety of RATS for thoracic neurogenic tumors.METHODS: This retrospective study is based on a prospectively created database that includes all RATS surgeries between 2018 and 2023. All patients with histologically confirmed neurogenic tumors were included in the study. The patients' medical and surgical records as well as radiological and pathological findings were analyzed.
RESULTS: During a 5-year period, 27 patients underwent robotic resection of neurogenic tumors at a high-volume thoracic surgery center. Two patients had previously undergone posterior laminectomy for resection of the intraspinal components. The pathologies included schwannomas (18, 64%), ganglioneuromas (8, 29%), 1 paraganglioma, and 1 neurofibroma occurring close to a schwannoma unilaterally in the same patient. The median tumor size was 4.7 cm (range 0.9-11.4 cm). The median operating time was 69 minutes (range 27-169 minutes), and the median postoperative stay was 3 days (range 1-19 days). There was one conversion due to adhesions after a previous surgery. No major bleeding occurred. There was no perioperative mortality. Morbidity included a lymphatic fistula (n = 1), pneumonia (n = 1), prolonged air leak (n = 1), and 4 cases of postoperative pain persisting for more than 4 weeks. Neurological complications were mostly observed in patients with tumors located at the thoracic apex: 2 cases of Horner's syndrome, 2 cases with compensatory hyperhidrosis, 1 patient with paresis of the recurrent laryngeal nerve, and a T1 lesion resulting in a minor motor deficit of the small hand muscles (Medical Research Council grade 4) and hypoesthesia of the respective dermatome.
CONCLUSIONS: RATS for thoracic neurogenic tumors is feasible and safe. Tumors at the thoracic apex are at high risk of neurological deficit and should be approached with care. Close interdisciplinary collaboration between neurosurgeons and thoracic surgeons is necessary for optimal patient selection and a good postoperative outcome.

Keywords: interdisciplinary surgery; minimally invasive surgery; neurogenic tumors; peripheral nerve; robotic surgery; tumor

DOI: https://doi.org/10.3171/2024.3.JNS232860

Anticancer Res. 2024 Jun;44(6): 2681-2687

Effect of Epidermal Growth Factor Receptor Mutation on Positron Emission Tomography/Computed Tomography in Lung Cancer.

Ji Sun Park, Ha Young Park, Yunseon Choi.

BACKGROUND/AIM: This study analyzed the effect of epidermal growth factor receptor (EGFR) mutations on fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (F-18 FDG PET/CT) results in lung cancer and the pathological findings in patients subjected to surgery.PATIENTS AND METHODS: A total of 210 patients diagnosed with lung cancer by F-18 FDG PET/CT at Inje University Busan Paik Hospital between January 2018 and December 2023 were recruited. EGFR mutation tests were performed on biopsy specimens. Overall, 78 patients (37.1%) with EGFR mutations were included in this study. Twenty-seven patients (12.9%) had distant metastases at the time of diagnosis. Of all patients, 69 (32.9%) underwent surgery at our hospital, and their pathological findings were analyzed.
RESULTS: The maximum standardized uptake value (SUVmax) of F-18 FDG PET/CT was <10 in patients with EGFR mutations. Patients with EGFR mutations were not commonly diagnosed with diabetes. When analyzing the pathological findings after surgery in the 69 patients, adenocarcinoma was more common in those with EGFR mutations. In contrast, perineural invasion was more common in patients without EGFR mutations. When analyzing the results of 69 patients with postoperative pathology, 25 relapsed during the median follow-up of 21.7 months (range=0.9-58.4 months). Patients who underwent surgery and had EGFR mutations (n=26) exhibited lower recurrence rates compared to those without EGFR mutations. Disease-free survival was longer in patients with EGFR mutations.
CONCLUSION: In non-small-cell lung cancer with an EGFR mutation, the F-18 FDG PET/CT SUVmax value and the probability of recurrence were lower. EGFR mutations are associated with low-glucose metabolism.

Keywords: EGFR mutation; PET; lung cancer; perineural invasion; recurrence

DOI: https://doi.org/10.21873/anticanres.17075