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Calcitonin Related Polypeptide Alpha Mediates Oral Cancer Pain

Tu, Nguyen Huu; Inoue, Kenji; Lewis, Parker K; Khan, Ammar; Hwang, Jun Hyeong; Chokshi, Varun; Dabovic, Branka Brukner; Selvaraj, Shanmugapriya; Bhattacharya, Aditi; Dubeykovskaya, Zinaida; Pinkerton, Nathalie M; Bunnett, Nigel W; Loomis, Cynthia A; Albertson, Donna G; Schmidt, Brian L
Oral cancer patients suffer pain at the site of the cancer. Calcitonin gene related polypeptide (CGRP), a neuropeptide expressed by a subset of primary afferent neurons, promotes oral cancer growth. CGRP also mediates trigeminal pain (migraine) and neurogenic inflammation. The contribution of CGRP to oral cancer pain is investigated in the present study. The findings demonstrate that CGRP-immunoreactive (-ir) neurons and neurites innervate orthotopic oral cancer xenograft tumors in mice. Cancer increases anterograde transport of CGRP in axons innervating the tumor, supporting neurogenic secretion as the source of CGRP in the oral cancer microenvironment. CGRP antagonism reverses oral cancer nociception in preclinical oral cancer pain models. Single-cell RNA-sequencing is used to identify cell types in the cancer microenvironment expressing the CGRP receptor components, receptor activity modifying protein 1 Ramp1 and calcitonin receptor like receptor (CLR, encoded by Calcrl). Ramp1 and Calcrl transcripts are detected in cells expressing marker genes for Schwann cells, endothelial cells, fibroblasts and immune cells. Ramp1 and Calcrl transcripts are more frequently detected in cells expressing fibroblast and immune cell markers. This work identifies CGRP as mediator of oral cancer pain and suggests the antagonism of CGRP to alleviate oral cancer pain.
PMID: 37443709
ISSN: 2073-4409
CID: 5535282

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.
PMID: 35925599
ISSN: 2701-0198
CID: 5289882

Engineering Fluorinated Thermo-responsive Assembled Protein (F-TRAP) for Theranostic Applications in Glioblastoma Multiforme [Meeting Abstract]

Bhattacharya, A; Mishkit, O; Tranos, J; Morales, L; Wang, A; Frenster, J; Bready, D; Boess, N; Lee, F; Wadghiri, Y; Placantonakis, D; Montclare, J K
Background Gliomas account for roughly 27% of all brain tumors and there is an urgent need to develop new therapeutic modalities. A glioblastoma multiforme (GBM) prognosis signifies a survival time of 14-16 months with only 5% of patients surviving more than 5 years. (1) A significant challenge for traditional GBM drug delivery is the inability to: a) treat tumor cells with cytotoxic drugs due to their poor solubility and lack of blood brain barrier (BBB) permeation; b) specifically target tumor cells while avoiding normal tissue with such cytotoxic agents c) stimulate drug release; and d) monitor GBM status and therapy non-invasively. (2) Theranostic agents are being developed for their ability to diagnose disease and improve therapeutic delivery and can address these requirements because treatments specific to GBM do not currently exist. (3) While considerable efforts have been made in developing protein-based systems as drug-delivery carriers or as diagnostic agents (4), we are investigating a fundamental new insight that is helping us develop a single protein-based system combining drug delivery capabilities with the ability to cross the BBB and remain at cancer site due to the enhanced permeation and retention (EPR) effect. This biomaterial also incorporates functional groups detectable via magnetic resonance (MR) spectroscopy and imaging as well as near-infrared fluorescence (NIR) to enable visualization during chemotherapy. The protein-based theranostic agent we have engineered is called fluorinated thermo-responsive assembled protein (F-TRAP) that bears a non-canonical fluorinated amino acid (trifluoroleucine or TFL), can self-assemble into micellar structures, and encapsulate hydrophobic drugs. Methods and Materials Circular dichroism and dynamic light scattering have been performed to observe F-TRAP's secondary structure and micelle formation respectively (2). Additionally, 19F magnetic resonance imaging (MRI) has been carried out to visualize F-TRAP (5) and near infra-red fluorescence imaging (NIRF) has been utilized to determine its pharmacokinetic properties in a glioblastoma (GBM) mouse model. Results Results indicate that F-TRAP has an ?-helical secondary structure and forms micelles 30 nm in size. F-TRAP shows favorable pharmacokinetic data with a half-life of 123 minutes and high plasma retention. Importantly, animal data also reveals the ability of F-TRAP to cross the BBB and to be imaged inside the brain. Conclusions F-TRAP is capable of encapsulating small hydrophobic molecules, such as dox. It crosses the BBB and undergoes EPR effect allowing it to accumulate therein and be visualized NIRF imaging and is capable of undergoing MR imaging due to an appropriate half-life of about 123 min
ISSN: 1860-2002
CID: 5512132

Peripheral nerve injury and sensitization underlie pain associated with oral cancer perineural invasion

Salvo, Elizabeth; Campana, Wendy M; Scheff, Nicole N; Tu, Nguyen Huu; Jeong, Se-Hee; Wall, Ian; Wu, Angie K; Zhang, Susanna; Kim, Hyesung; Bhattacharya, Aditi; Janal, Malvin N; Liu, Cheng; Albertson, Donna G; Schmidt, Brian L; Dolan, John C; Schmidt, Robert E; Boada, M Danilo; Ye, Yi
Cancer invading into nerves, termed perineural invasion (PNI), is associated with pain. Here we show that oral cancer patients with PNI report greater spontaneous pain and mechanical allodynia compared with patients without PNI, suggesting unique mechanisms drive PNI-induced pain. We studied the impact of PNI on peripheral nerve physiology and anatomy using a murine sciatic nerve PNI model. Mice with PNI exhibited spontaneous nociception and mechanical allodynia. PNI induced afterdischarge in A high threshold mechanoreceptors (AHTMRs), mechanical sensitization (i.e., decreased mechanical thresholds) in both A and C HTMRs, and mechanical desensitization in low threshold mechanoreceptors (LTMRs). PNI resulted in nerve damage, including axon loss, myelin damage, and axon degeneration. Electrophysiological evidence of nerve injury included decreased conduction velocity, and increased percentage of both mechanically-insensitive and electrically-unexcitable neurons. We conclude that PNI-induced pain is driven by nerve injury and peripheral sensitization in HTMRs.
PMID: 32658150
ISSN: 1872-6623
CID: 4527892

The Histopathology of Oral Cancer Pain in a Mouse Model and a Human Cohort

Naik, K; Janal, M N; Chen, J; Bandary, D; Brar, B; Zhang, S; Dolan, J C; Schmidt, B L; Albertson, D G; Bhattacharya, A
Oral cancer patients often have severe, chronic, and mechanically induced pain at the site of the primary cancer. Oral cancer pain is initiated and maintained in the cancer microenvironment and attributed to release of mediators that sensitize primary sensory nerves. This study was designed to investigate the histopathology associated with painful oral cancers in a preclinical model. The relationship of pain scores with pathologic variables was also investigated in a cohort of 72 oral cancer patients. Wild-type mice were exposed to the carcinogen, 4-nitroquinoline 1-oxide (4NQO). Nociceptive (pain) behavior was measured with the dolognawmeter, an operant device and assay for measuring functional and mechanical allodynia. Lesions developed on the tongues and esophagi of the 4NQO-treated animals and included hyperkeratoses, papillomas, dysplasias, and cancers. Papillomas included lesions with benign and dysplastic pathological features. Two histologic subtypes of squamous cell carcinomas (SCCs) were identified-SCCs with exophytic and invasive components associated with papillary lesions (pSCCs) and invasive SCCs without exophytic histology (iSCCs). Only the pSCC subtype of tongue cancer was associated with nociceptive behavior. Increased tumor size was associated with greater nociceptive behavior in the mouse model and more pain experienced by oral cancer patients. In addition, depth of invasion was associated with patient-reported pain. The pSCC histology identifies 4NQO-induced tongue cancers that are expected to be enriched for expression and release of nociceptive mediators.
PMID: 33030108
ISSN: 1544-0591
CID: 4631562

Oncogenes overexpressed in metastatic oral cancers from patients with pain: potential pain mediators released in exosomes

Bhattacharya, Aditi; Janal, Malvin N; Veeramachaneni, Ratna; Dolgalev, Igor; Dubeykovskaya, Zinaida; Tu, Nguyen Huu; Kim, Hyesung; Zhang, Susanna; Wu, Angie K; Hagiwara, Mari; Kerr, A Ross; DeLacure, Mark D; Schmidt, Brian L; Albertson, Donna G
Oral cancer patients experience pain at the site of the primary cancer. Patients with metastatic oral cancers report greater pain. Lack of pain identifies patients at low risk of metastasis with sensitivity = 0.94 and negative predictive value = 0.89. In the same cohort, sensitivity and negative predictive value of depth of invasion, currently the best predictor, were 0.95 and 0.92, respectively. Cancer pain is attributed to cancer-derived mediators that sensitize neurons and is associated with increased neuronal density. We hypothesized that pain mediators would be overexpressed in metastatic cancers from patients reporting high pain. We identified 40 genes overexpressed in metastatic cancers from patients reporting high pain (n = 5) compared to N0 cancers (n = 10) and normal tissue (n = 5). The genes are enriched for functions in extracellular matrix organization and angiogenesis. They have oncogenic and neuronal functions and are reported in exosomes. Hierarchical clustering according to expression of neurotrophic and axon guidance genes also separated cancers according to pain and nodal status. Depletion of exosomes from cancer cell line supernatant reduced nociceptive behavior in a paw withdrawal assay, supporting a role for exosomes in cancer pain. The identified genes and exosomes are potential therapeutic targets for stopping cancer and attenuating pain.
PMID: 32895418
ISSN: 2045-2322
CID: 4588822

Oral Cancer: Genetics and the Role of Precision Medicine

Li, Chia-Cheng; Shen, Zhen; Bavarian, Roxanne; Yang, Fan; Bhattacharya, Aditi
Oral squamous cell carcinoma (OSCC) is one of the leading cancers in the world. OSCC patients are managed with surgery and/or chemoradiation. Prognoses and survival rates are dismal, however, and have not improved for more than 20 years. Recently, the concept of precision medicine was introduced, and the introduction of targeted therapeutics demonstrated promising outcomes. This article reviews the current understanding of initiation, progression, and metastasis of OSCC from both genetic and epigenetic perspectives. In addition, the applications and integration of omics technologies in biomarker discovery and drug development for treating OSCC are reviewed.
PMID: 31757309
ISSN: 1558-5042
CID: 4216642

Oral cancer pain mediators released in exosomes are oncogenes with potential to shape the microenvironment and induce neuronal sensitivity [Meeting Abstract]

Bhattacharya, Aditi; Dubeykoskaya, Zinaida; Nguyen, Huu Tu; Dolgalev, Igor; Veeramachaneni, Ratna; Schmidt, Brian L.; Albertson, Donna G.
ISSN: 0008-5472
CID: 4820802

Lesion pathology and oral-cancer associated pain in the 4NQO oral carcinogenesis model [Meeting Abstract]

Naik, Keyur; Janal, Malvin N.; Chen, Jason; Bandary, Daniel E.; Brar, Branden; Bhattacharya, Aditi
ISSN: 0008-5472
CID: 4820792

Protease-activated receptor-2 in endosomes signals persistent pain of irritable bowel syndrome

Jimenez-Vargas, Nestor N; Pattison, Luke A; Zhao, Peishen; Lieu, TinaMarie; Latorre, Rocco; Jensen, Dane D; Castro, Joel; Aurelio, Luigi; Le, Giang T; Flynn, Bernard; Herenbrink, Carmen Klein; Yeatman, Holly R; Edgington-Mitchell, Laura; Porter, Christopher J H; Halls, Michelle L; Canals, Meritxell; Veldhuis, Nicholas A; Poole, Daniel P; McLean, Peter; Hicks, Gareth A; Scheff, Nicole; Chen, Elyssa; Bhattacharya, Aditi; Schmidt, Brian L; Brierley, Stuart M; Vanner, Stephen J; Bunnett, Nigel W
Once activated at the surface of cells, G protein-coupled receptors (GPCRs) redistribute to endosomes, where they can continue to signal. Whether GPCRs in endosomes generate signals that contribute to human disease is unknown. We evaluated endosomal signaling of protease-activated receptor-2 (PAR2), which has been proposed to mediate pain in patients with irritable bowel syndrome (IBS). Trypsin, elastase, and cathepsin S, which are activated in the colonic mucosa of patients with IBS and in experimental animals with colitis, caused persistent PAR2-dependent hyperexcitability of nociceptors, sensitization of colonic afferent neurons to mechanical stimuli, and somatic mechanical allodynia. Inhibitors of clathrin- and dynamin-dependent endocytosis and of mitogen-activated protein kinase kinase-1 prevented trypsin-induced hyperexcitability, sensitization, and allodynia. However, they did not affect elastase- or cathepsin S-induced hyperexcitability, sensitization, or allodynia. Trypsin stimulated endocytosis of PAR2, which signaled from endosomes to activate extracellular signal-regulated kinase. Elastase and cathepsin S did not stimulate endocytosis of PAR2, which signaled from the plasma membrane to activate adenylyl cyclase. Biopsies of colonic mucosa from IBS patients released proteases that induced persistent PAR2-dependent hyperexcitability of nociceptors, and PAR2 association with β-arrestins, which mediate endocytosis. Conjugation to cholestanol promoted delivery and retention of antagonists in endosomes containing PAR2 A cholestanol-conjugated PAR2 antagonist prevented persistent trypsin- and IBS protease-induced hyperexcitability of nociceptors. The results reveal that PAR2 signaling from endosomes underlies the persistent hyperexcitability of nociceptors that mediates chronic pain of IBS. Endosomally targeted PAR2 antagonists are potential therapies for IBS pain. GPCRs in endosomes transmit signals that contribute to human diseases.
PMID: 30012612
ISSN: 1091-6490
CID: 3201962