ArticleInternational journal of radiation oncology, biology, physics2023
Radiation Therapy Exacerbates Tumor-Promoting Innervation and Nerve Signaling in Rectal Cancer.
Article in International journal of radiation oncology, biology, physics, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers, 1 of them a synthesis that pooled it.
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Who cites it
9 citing papers in PubMed, 1 synthesis or guideline pooled it, 12 citations in OpenAlex.
- The accuracy of radiomics in diagnosing tumor deposits and perineural invasion in rectal cancer: a systematic review and meta-analysis.Frontiers in oncology · 2024Pooled it
- Review
- Tumor-Infiltrating Nociceptor Neurons in Ovarian Cancer Treatment Resistance.Advanced biology · 2026Article
- Diagnostic efficacy of dual-energy computed tomography-based fractal analysis for assessing extramural venous invasion/tumor deposits and peripheral nerve invasion in rectal cancer.Quantitative imaging in medicine and surgery · 2026Article
- The role of the tumor microenvironment in mediating radiopharmaceutical therapy: bridging nuclear medicine and cancer immunotherapy.Military Medical Research · 2026Review
- Reprogramming neural-tumor crosstalk: emerging therapeutic dimensions and targeting strategies.Military Medical Research · 2025Review
- Recent advances in the development and application of colorectal cancer mouse models.Frontiers in pharmacology · 2025Review
- New insights into the responder/nonresponder divide in rectal cancer: Damage-induced Type I IFNs dictate treatment efficacy and can be targeted to enhance radiotherapy.Cell death & disease · 2023Article
- New insights into the responder/nonresponder divide in rectal cancer: Damage-induced Type I IFNs dictate treatment efficacy and can be targeted to enhance radiotherapy.Research square · 2023Article
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Authors and funding
20 authors at 3 institutions in 1 country.
Funding
Abstract
purposeMany solid tumors present with perineural invasion (PNI), and innervation correlates with worsened prognosis. The effects that commonly administered therapies such as radiation therapy (RT) have on PNI status remain unknown. We investigated the contribution of RT on the nervous system and elucidated the implications that increased nerve signaling can have on tumor burden using our previously developed orthotopic murine model of rectal cancer (RC) and our targeted and clinically relevant short-course RT (SCRT) regimen.
methodsMedical charts for patients with RC treated at the Wilmot Cancer Institute were obtained and PNI status was analyzed. Human data were accompanied by an orthotopic murine model of RC. Briefly, luciferase-expressing murine colon-38 (MC38-luc) tumor cells were injected orthotopically into the rectal wall of C57BL6 mice. Targeted SCRT (5 gray (Gy) per fraction for 5 consecutive fractions) was administered to the tumor. Intratumoral innervation was determined by immunohistochemistry (IHC), local norepinephrine (NE) concentration was quantified by enzyme-linked immunosorbent assay (ELISA), and β2-adrenergic receptor (B2AR) expression was assessed by flow cytometry. Chronic NE signaling was mirrored by daily isoproterenol treatment, and the effect on tumor burden was determined by overall survival, presence of metastatic lesions, and tumor size. Isoproterenol signaling was inhibited by administration of propranolol.
resultsHuman RC patients with PNI have decreased overall survival compared with patients without PNI. In our mouse model, SCRT induced the expression of genes involved in neurogenesis, increased local NE secretion, and upregulated B2AR expression. Treating mice with isoproterenol resulted in decreased overall survival, increased rate of metastasis, and reduced SCRT efficacy. Interestingly, the isoproterenol-induced decrease in SCRT efficacy could be abrogated by blocking the BAR through the use of propranolol, suggesting a direct role of BAR stimulation on impairing SCRT responses.
conclusionsOur results indicate that while SCRT is a valuable treatment, it is accompanied by adverse effects on the nervous system that may impede the efficacy of therapy and promote tumor burden. Therefore, we could speculate that therapies aimed at targeting this signaling cascade or impairing nerve growth in combination with SCRT may prove beneficial in future cancer treatment.
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