Metastatic model of HPV+ oropharyngeal squamous cell carcinoma demonstrates heterogeneity in tumor metastasis
| Autor: | William C. Spanos, Joseph D. Coppock, Kimberly M. Lee, John H. Lee, Ravindra Uppaluri, Erliang Zeng, Daniel W. Vermeer, Michael D. Onken, Paola D. Vermeer |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Oncology Pathology Microarray Apoptosis Disease Metastasis Mice 0302 clinical medicine Cell Movement Neoplasms Antineoplastic Combined Chemotherapy Protocols Tumor Cells Cultured Medicine Prospective Studies human papillomavirus Aged 80 and over Mice Inbred BALB C Cell Cycle Middle Aged Cell cycle Prognosis Combined Modality Therapy 3. Good health Survival Rate Lymphatic system Lymphatic Metastasis 030220 oncology & carcinogenesis Female Research Paper medicine.drug Adult medicine.medical_specialty recurrence Mice Nude 03 medical and health sciences Internal medicine Biomarkers Tumor Cell Adhesion metastasis Animals Humans Neoplasm Invasiveness Survival rate Aged Cell Proliferation Cisplatin business.industry Cancer medicine.disease Xenograft Model Antitumor Assays Mice Inbred C57BL 030104 developmental biology Case-Control Studies Neoplasm Recurrence Local head and neck oral cancer business Follow-Up Studies |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| DOI: | 10.18632/oncotarget.8254 |
| Popis: | // Daniel W. Vermeer 1 , Joseph D. Coppock 1 , Erliang Zeng 2, 3 , Kimberly M. Lee 1 , William C. Spanos 1, 4 , Michael D. Onken 5 , Ravindra Uppaluri 6 , John H. Lee 1, 4 , Paola D. Vermeer 1 1 Cancer Biology Research Center, Sanford Research, Sioux Falls, South Dakota, USA 2 Department of Biology, University of South Dakota, Vermillion, South Dakota, USA 3 Department of Computer Science, University of South Dakota, Vermillion, South Dakota, USA 4 Department of Otolaryngology/Head and Neck Surgery, Sanford Health, Sioux Falls, South Dakota, USA 5 Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri, USA 6 Otolaryngology, Washington University School of Medicine, St. Louis, Missouri, USA Correspondence to: Paola D. Vermeer, e-mail: Paola.Vermeer@SanfordHealth.org Keywords: head and neck oral cancer, human papillomavirus, metastasis, recurrence Received: October 19, 2015 Accepted: March 06, 2016 Published: March 22, 2016 ABSTRACT Human papillomavirus induced (HPV+) cancer incidence is rapidly rising, comprising 60–80% of oropharyngeal squamous cell carcinomas (OPSCCs); while rare, recurrent/metastatic disease accounts for nearly all related deaths. An in vivo pre-clinical model for these invasive cancers is necessary for testing new therapies. We characterize an immune competent recurrent/metastatic HPV+ murine model of OPSSC which consists of four lung metastatic (MLM) cell lines isolated from an animal with HPV+ OPSCC that failed cisplatin/radiation treatment. These individual metastatic clonal cell lines were tested to verify their origin (parental transgene expression and define their physiological properties: proliferation, metastatic potential, heterogeneity and sensitivity/resistance to cisplatin and radiation. All MLMs retain expression of parental HPV16 E6 and E7 and degrade P53 yet are heterogeneous from one another and from the parental cell line as defined by Illumina expression microarray. Consistent with this, reverse phase protein array defines differences in protein expression/activation between MLMs as well as the parental line. While in vitro growth rates of MLMs are slower than the parental line, in vivo growth of MLM clones is greatly enhanced. Moreover, in vivo resistance to standard therapies is dramatically increased in 3 of the 4 MLMs. Lymphatic and/or lung metastasis occurs 100% of the time in one MLM line. This recurrent/metastatic model of HPV+ OPSCC retains the characteristics evident in refractory human disease (heterogeneity, resistance to therapy, metastasis in lymph nodes/lungs) thus serving as an ideal translational system to test novel therapeutics. Moreover, this system may provide insights into the molecular mechanisms of metastasis. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|