Peroxisome proliferator-activated receptor gamma agonist ELB00824 suppresses oxaliplatin-induced pain, neuronal hypersensitivity, and oxidative stress
Zhang, Morgan; Hu, Min; Alles, Sascha R A; Montera, Marena A; Adams, Ian; Santi, Maria D; Inoue, Kenji; Tu, Nguyen Huu; Westlund, Karin N; Ye, Yi
Chemotherapy-induced neuropathic pain (CINP) is a debilitating and difficult-to-treat side effect of chemotherapeutic drugs. CINP is marked with oxidative stress and neuronal hypersensitivities. The peroxisome proliferator-activated receptor gamma (PPARÎ³) is a transcription factor that regulates genes involved in oxidative stress and inflammation. We hypothesize that PPARÎ³ agonists are protective against CIPN by reducing oxidative stress and inhibiting neuronal hypersensitivities. To test our hypothesis, acute or chronic CIPN was introduced by short or long-term treatment of oxaliplatin in BALB/c mice. CIPN mice were treated with either a novel blood-brain barrier (BBB) penetrable PPARÎ³ agonist ELB00824, or a BBB non-penetrable PPARÎ³ agonist pioglitazone, or vehicle. Cold allodynia, mechanical allodynia, motor coordination, sedation and addiction were measured with dry ice, von Frey filaments, beam-walking tests, and conditioned place preference, respectively. Oxidative stress was accessed by measuring byproducts of protein oxidation (carbonyl and 3-Nitrotyrosine) and lipid peroxidation [Thiobarbituric acid reactive substances (TBARS)], as wells as gene expression of Cat, Sod2, Ppargc1a. The effects of ELB00824 on nociceptor excitability were measured using whole-cell electrophysiology of isolated dorsal root ganglion neurons. Preemptive ELB00824, but not pioglitazone, reduced oxaliplatin-induced cold and mechanical allodynia and oxidative stress. ELB0824 suppressed oxaliplatin-induced firing in IB4- neurons. ELB00824 did not cause motor discoordination or sedation/addiction or reduce the antineoplastic activity of oxaliplatin (measured with an MTS-based cell proliferation assay) in a human colon cancer cell line (HCT116) and a human oral cancer cell line (HSC-3). Our results demonstrated that ELB00824 prevents oxaliplatin-induced pain, likely via inhibiting neuronal hypersensitivities and oxidative stress.
Distinct immune signature predicts progression of vestibular schwannoma and unveils a possible viral etiology
Amit, Moran; Xie, Tongxin; Gleber-Netto, Frederico O; Hunt, Patrick J; Mehta, Gautam U; Bell, Diana; Silverman, Deborah A; Yaman, Ismail; Ye, Yi; Burks, Jared K; Fuller, Gregory N; Gidley, Paul W; Nader, Marc-Elie; Raza, Shaan M; DeMonte, Franco
BACKGROUND:The management of sub-totally resected sporadic vestibular schwannoma (VS) may include observation, re-resection or irradiation. Identifying the optimal choice can be difficult due to the disease's variable progression rate. We aimed to define an immune signature and associated transcriptomic fingerprint characteristic of rapidly-progressing VS to elucidate the underpinnings of rapidly progressing VS and identify a prognostic model for determining rate of progression. METHODS:We used multiplex immunofluorescence to characterize the immune microenvironment in 17 patients with sporadic VS treated with subtotal surgical resection alone. Transcriptomic analysis revealed differentially-expressed genes and dysregulated pathways when comparing rapidly-progressing VS to slowly or non-progressing VS. RESULTS:immune cells. RNA data indicated the upregulation of anti-viral innate immune response and T-cell senescence. Kâ€‰-â€‰Top Scoring Pair analysis identified 6 pairs of immunosenescence-related genes (CD38-KDR, CD22-STAT5A, APCS-CXCR6, MADCAM1-MPL, IL6-NFATC3, and CXCL2-TLR6) that had high sensitivity (100%) and specificity (78%) for identifying rapid VS progression. CONCLUSION/CONCLUSIONS:Rapid progression of residual vestibular schwannoma following subtotal surgical resection has an underlying immune etiology that may be virally originating; and despite an abundant adaptive immune response, T-cell immunosenescence may be associated with rapid progression of VS. These findings provide a rationale for clinical trials evaluating immunotherapy in patients with rapidly progressing VS.
Neurotrophin Pathway Receptors NGFR and TrkA Control Perineural Invasion, Metastasis, and Pain in Oral Cancer
Doan, Coleen; Aouizerat, Bradley E; Ye, Yi; Dang, Dongmin; Asam, Kesava; Bhattacharya, Aditi; Howard, Timothy; Patel, Yogin K; Viet, Dan T; Figueroa, Johnny D; Zhong, Jiang F; Thomas, Carissa M; Morlandt, Anthony B; Yu, Gary; Callahan, Nicholas F; Allen, Clint T; Grandhi, Anupama; Herford, Alan S; Walker, Paul C; Nguyen, Khanh; Kidd, Stephanie C; Lee, Steve C; Inman, Jared C; Slater, Jason M; Viet, Chi T
Oral squamous cell carcinoma (OSCC) patients suffer from poor survival due to metastasis or locoregional recurrence, processes that are both facilitated by perineural invasion (PNI). OSCC has higher rates of PNI than other cancer subtypes, with PNI present in 80% of tumors. Despite the impact of PNI on oral cancer prognosis and pain, little is known about the genes that drive PNI, which in turn drive pain, invasion, and metastasis. In this study, clinical data, preclinical, and in vitro models are leveraged to elucidate the role of neurotrophins in OSCC metastasis, PNI, and pain. The expression data in OSCC patients with metastasis, PNI, or pain demonstrate dysregulation of neurotrophin genes. TrkA and nerve growth factor receptor (NGFR) are focused, two receptors that are activated by NGF, a neurotrophin expressed at high levels in OSCC. It is demonstrated that targeted knockdown of these two receptors inhibits proliferation and invasion in an in vitro and preclinical model of OSCC, and metastasis, PNI, and pain. It is further determined that TrkA knockdown alone inhibits thermal hyperalgesia, whereas NGFR knockdown alone inhibits mechanical allodynia. Collectively the results highlight the ability of OSCC to co-opt different components of the neurotrophin pathway in metastasis, PNI, and pain.
Schwann Cells Induce Phenotypic Changes in Oral Cancer Cells
Santi, Maria Daniela; Zhang, Morgan; Salvo, Elizabeth; Asam, Kesava; Viet, Chi T; Xie, Tongxin; Amit, Moran; Aouizerat, Bradley; Ye, Yi
Head and neck cancer (HNC) is the seventh most common cancer worldwide, the majority being oral squamous cell carcinoma. Despite advances in cancer diagnosis and treatment, the survival rate of patients with HNC remains stagnant. The cancer-nerve interaction has been recognized as an importantÂ driver of cancer progression. Schwann cells, a type of peripheral glia, have been implicated in promoting cancer cell growth, migration, dispersion, and invasion into the nerve in many cancers. Here, it is demonstrated that the presence of Schwann cells makes oral cancer cells more aggressiveÂ by promoting their proliferation, extracellular matrix breakdown, and altering cell metabolism. Furthermore, oral cancer cells became larger, more circular, with more projections and nuclei following co-culturing with Schwann cells. RNA-sequencing analysis in oral cancer cells following exposure to Schwann cells shows corresponding changes in genes involved in the hallmarks of cancer and cell metabolism; the enriched KEGG pathways are spliceosome, RNA transport, cell cycle, axon guidance, signaling pathways regulating pluripotency of stem cells, cAMP signaling, WNT signaling, proteoglycans in cancer and PI3K-Akt signaling. Taken together, these results suggest a significant role for Schwann cells in facilitating oral cancer progression, highlighting their potential as a target to treat oral cancer progression.
Advances in understanding cancer-associated neurogenesis and its implications on the neuroimmune axis in cancer
Yaman, Ismail; Ã‡obanoÄŸlu, Didem AÄŸaÃ§; Xie, Tongxin; Ye, Yi; Amit, Moran
Nerves and immunologic mediators play pivotal roles in body homeostasis by interacting with each other through diverse mechanisms. The spread of nerves in the tumor microenvironment increases tumor cell proliferation and disease progression, and this correlates with poor patient outcomes. The effects of sympathetic and parasympathetic nerves on cancer regulation are being investigated. Recent findings demonstrate the possibility of developing therapeutic strategies that target the tumor microenvironment and its components such as immune cells, neurotransmitters, and extracellular vesicles. Therefore, examining and understanding the mechanisms and pathways associated with the sympathetic and parasympathetic nervous systems, neurotransmitters, cancer-derived mediators and their interactions with the immune system in the tumor microenvironment may lead to the development of new cancer treatments. This review discusses the effects of nerve cells, immune cells, and cancer cells have on each other that regulate neurogenesis, cancer progression, and dissemination.
Advances in Head and Neck Cancer Pain
Ye, Y; Jensen, D D; Viet, C T; Pan, H L; Campana, W M; Amit, M; Boada, M D
Head and neck cancer (HNC) affects over 890,000 people annually worldwide and has a mortality rate of 50%. Aside from poor survival, HNC pain impairs eating, drinking, and talking in patients, severely reducing quality of life. Different pain phenotype in patients (allodynia, hyperalgesia, and spontaneous pain) results from a combination of anatomical, histopathological, and molecular differences between cancers. Poor pathologic features (e.g., perineural invasion, lymph node metastasis) are associated with increased pain. The use of syngeneic/immunocompetent animal models, as well as a new mouse model of perineural invasion, provides novel insights into the pathobiology of HNC pain. Glial and immune modulation of the tumor microenvironment affect not only cancer progression but also pain signaling. For example, Schwann cells promote cancer cell proliferation, migration, and secretion of nociceptive mediators, whereas neutrophils are implicated in sex differences in pain in animal models of HNC. Emerging evidence supports the existence of a functional loop of cross-activation between the tumor microenvironment and peripheral nerves, mediated by a molecular exchange of bioactive contents (pronociceptive and protumorigenic) via paracrine and autocrine signaling. Brain-derived neurotrophic factor, tumor necrosis factor Î±, legumain, cathepsin S, and A disintegrin and metalloprotease 17 expressed in the HNC microenvironment have recently been shown to promote HNC pain, further highlighting the importance of proinflammatory cytokines, neurotrophic factors, and proteases in mediating HNC-associated pain. Pronociceptive mediators, together with nerve injury, cause nociceptor hypersensitivity. Oncogenic, pronociceptive mediators packaged in cancer cell-derived exosomes also induce nociception in mice. In addition to increased production of pronociceptive mediators, HNC is accompanied by a dampened endogenous antinociception system (e.g., downregulation of resolvins and Âµ-opioid receptor expression). Resolvin treatment or gene delivery of Âµ-opioid receptors provides pain relief in preclinical HNC models. Collectively, recent studies suggest that pain and HNC progression share converging mechanisms that can be targeted for cancer treatment and pain management.
Altered Prevalence of Pulp Diagnoses in Diabetes Mellitus Patients: A Retrospective Study
Gonzalez Marrero, Yandy; Kobayashi, Yoshifumi; Ihsan, Mohammad Saqib; Pilch, Lisa A; Chen, Liyaa; Jiang, Shuying; Ye, Yi; Fine, Daniel H; Falcon, Carla Y; Falcon, Paul A; Hirschberg, Craig S; Shimizu, Emi
INTRODUCTION/BACKGROUND:Diabetes mellitus (DM) is a complex multisystemic disorder that affects an estimated 21 million Americans. No studies have evaluated the association of DM with the prevalence of each pulpal diagnosis. The objective of this study was to compare the prevalence of each pulp diagnosis including symptomatic irreversible pulpitis (SIP), asymptomatic irreversible pulpitis, reversible pulpitis, normal pulp, and pulp necrosis (PN) in DM patients against a nondiabetic control group. METHODS:A retrospective chart review was approved by Rutgers University Institutional Review Board. The prevalence of the diagnoses SIP, asymptomatic irreversible pulpitis, reversible pulpitis, normal pulp, and PN was calculated from AxiUm (Exan software, Las Vegas, NV) electronic health records at Rutgers School of Dental Medicine. The chi-square test was used to see the relationship between the 2 categoric variables. Second, binary logistic regression analyses were performed for each group. RESULTS:A total of 2979 teeth were diagnosed with a pulp condition between April 2013 and November 2018. The total tooth number of DM patients was 682, whereas the tooth number of nondiabetic patients was 2297. In the subgroup of patients younger than 40Â years old, SIP was notably more prevalent in DM patients. In addition, the prevalence of PN in elderly DM patients (60-69Â years old) was significantly higher than in the control group. CONCLUSIONS:The prevalence of SIP in DM patients was significantly higher compared with the control group (<40Â years old), suggesting the possibility that DM could hypersensitize the subgroup of patients younger than 40Â years old to pulpitis pain.
Glia and Orofacial Pain: Progress and Future Directions
Ye, Yi; Salvo, Elizabeth; Romero-Reyes, Marcela; Akerman, Simon; Shimizu, Emi; Kobayashi, Yoshifumi; Michot, Benoit; Gibbs, Jennifer
Orofacial pain is a universal predicament, afflicting millions of individuals worldwide. Research on the molecular mechanisms of orofacial pain has predominately focused on the role of neurons underlying nociception. However, aside from neural mechanisms, non-neuronal cells, such as Schwann cells and satellite ganglion cells in the peripheral nervous system, and microglia and astrocytes in the central nervous system, are important players in both peripheral and central processing of pain in the orofacial region. This review highlights recent molecular and cellular findings of the glia involvement and glia-neuron interactions in four common orofacial pain conditions such as headache, dental pulp injury, temporomandibular joint dysfunction/inflammation, and head and neck cancer. We will discuss the remaining questions and future directions on glial involvement in these four orofacial pain conditions.
TNFÎ± promotes oral cancer growth, pain, and Schwann cell activation
Salvo, Elizabeth; Tu, Nguyen H; Scheff, Nicole N; Dubeykovskaya, Zinaida A; Chavan, Shruti A; Aouizerat, Bradley E; Ye, Yi
Oral cancer is very painful and impairs a patient's ability to eat, talk, and drink. Mediators secreted from oral cancer can excite and sensitize sensory neurons inducing pain. Cancer mediators can also activate Schwann cells, the peripheral glia that regulates neuronal function and repair. The contribution of Schwann cells to oral cancer pain is unclear. We hypothesize that the oral cancer mediator TNFÎ± activates Schwann cells, which further promotes cancer progression and pain. We demonstrate that TNFÎ± is overexpressed in human oral cancer tissues and correlates with increased self-reported pain in patients. Antagonizing TNFÎ± reduces oral cancer proliferation, cytokine production, and nociception in mice with oral cancer. Oral cancer or TNFÎ± alone increases Schwann cell activation (measured by Schwann cell proliferation, migration, and activation markers), which can be inhibited by neutralizing TNFÎ±. Cancer- or TNFÎ±-activated Schwann cells release pro-nociceptive mediators such as TNFÎ± and nerve growth factor (NGF). Activated Schwann cells induce nociceptive behaviors in mice, which is alleviated by blocking TNFÎ±. Our study suggests that TNFÎ± promotes cancer proliferation, progression, and nociception at least partially by activating Schwann cells. Inhibiting TNFÎ± or Schwann cell activation might serve as therapeutic approaches for the treatment of oral cancer and associated pain.
Targeting the endothelin axis as a therapeutic strategy for oral cancer metastasis and pain
Dang, Dongmin; Ye, Yi; Aouizerat, Bradley E; Patel, Yogin K; Viet, Dan T; Chan, King Chong; Ono, Kentaro; Doan, Coleen; Figueroa, Johnny D; Yu, Gary; Viet, Chi T
Metastasis reduces survival in oral cancer patients and pain is their greatest complaint. We have shown previously that oral cancer metastasis and pain are controlled by the endothelin axis, which is a pathway comprised of the endothelin A and B receptors (ETAR and ETBR). In this study we focus on individual genes of the pathway, demonstrating that the endothelin axis genes are methylated and dysregulated in cancer tissue. Based on these findings in patients, we hypothesize that ETAR and ETBR play dichotomous roles in oral carcinogenesis and pain, such that ETAR activation and silenced ETBR expression result in increased carcinogenesis and pain. We test a treatment strategy that targets the dichotomous functions of the two receptors by inhibiting ETAR with macitentan, an ETAR antagonist approved for treatment of pulmonary hypertension, and re-expressing the ETBR gene with adenovirus transduction, and determine the treatment effect on cancer invasion (i.e., metastasis), proliferation and pain in vitro and in vivo. We demonstrate that combination treatment of macitentan and ETBR gene therapy inhibits invasion, but not proliferation, in cell culture and in a mouse model of tongue cancer. Furthermore, the treatment combination produces an antinociceptive effect through inhibition of endothelin-1 mediated neuronal activation, revealing the analgesic potential of macitentan. Our treatment approach targets a pathway shown to be dysregulated in oral cancer patients, using gene therapy and repurposing an available drug to effectively treat both oral cancer metastasis and pain in a preclinical model.