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Modeling metastasis biology and therapy in real time in the mouse lung.

ABSTRACT: Pulmonary metastasis remains the leading ca use of death for cancer patients. Opportunities to improve treatment outcomes for patients require new methods to study and view the biology of metastatic progression. Here, we describe an ex vivo pulmonary metastasis assay (PuMA) in which the metastatic progression of GFP-expressing cancer cells, from a single cell to the formation of multicellular colonies, in the mouse lung microenvironment was assessed in real time for up to 21 days. The biological validity of this assay was confirmed by its prediction of the in vivo behavior of a variety of high- and low-metastatic human and mouse cancer cell lines and the discrimination of tumor microenvironments in the lung that were most permissive to metastasis. Using this approach, we provide what we believe to be new insights into the importance of tumor cell interactions with the stromal components of the lung microenvironment. Finally, the translational utility of this assay was demonstrated through its use in the evaluation of therapeutics at discrete time points during metastatic progression. We believe that this assay system is uniquely capable of advancing our understanding of both metastasis biology and therapeutic strategies.

SUBMITTER: Mendoza A

PROVIDER: S-EPMC2912183 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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Modeling metastasis biology and therapy in real time in the mouse lung.

Mendoza Arnulfo A Hong Sung-Hyeok SH Osborne Tanasa T Khan Mohammed A MA Campbell Kirk K Briggs Joseph J Eleswarapu Ananth A Buquo Lauren L Ren Ling L Hewitt Stephen M SM Dakir El Habib el H Garfield Susan S Walker Renard R Merlino Glenn G Green Jeffrey E JE Hunter Kent W KW Wakefield Lalage M LM Khanna Chand C

The Journal of clinical investigation 20100719 8

Pulmonary metastasis remains the leading ca use of death for cancer patients. Opportunities to improve treatment outcomes for patients require new methods to study and view the biology of metastatic progression. Here, we describe an ex vivo pulmonary metastasis assay (PuMA) in which the metastatic progression of GFP-expressing cancer cells, from a single cell to the formation of multicellular colonies, in the mouse lung microenvironment was assessed in real time for up to 21 days. The biological ...[more]

PMID: 20644255

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Project description:Osteosarcoma is a malignant primary tumor of bone, arising from transformed progenitor cells with osteoblastic differentiation and osteoid production. While categorized as a rare tumor, most patients diagnosed with osteosarcoma are adolescents in their second decade of life and underscores the potential for life changing consequences in this vulnerable population. In the setting of localized disease, conventional treatment for osteosarcoma affords a cure rate approaching 70%; however, survival for patients suffering from metastatic disease remain disappointing with only 20% of individuals being alive past 5 years post-diagnosis. In patients with incurable disease, pulmonary metastases remain the leading cause for osteosarcoma-associated mortality; yet identifying new strategies for combating metastatic progression remains at a scientific and clinical impasse, with no significant advancements for the past four decades. While there is resonating clinical urgency for newer and more effective treatment options for managing osteosarcoma metastases, the discovery of druggable targets and development of innovative therapies for inhibiting metastatic progression will require a deeper and more detailed understanding of osteosarcoma metastasis biology. Toward the goal of illuminating the processes involved in cancer metastasis, a convergent science approach inclusive of diverse disciplines spanning the biology and physical science domains can offer novel and synergistic perspectives, inventive, and sophisticated model systems, and disruptive experimental approaches that can accelerate the discovery and characterization of key processes operative during metastatic progression. Through the lens of trans-disciplinary research, the field of comparative oncology is uniquely positioned to advance new discoveries in metastasis biology toward impactful clinical translation through the inclusion of pet dogs diagnosed with metastatic osteosarcoma. Given the spontaneous course of osteosarcoma development in the context of real-time tumor microenvironmental cues and immune mechanisms, pet dogs are distinctively valuable in translational modeling given their faithful recapitulation of metastatic disease progression as occurs in humans. Pet dogs can be leveraged for the exploration of novel therapies that exploit tumor cell vulnerabilities, perturb local microenvironmental cues, and amplify immunologic recognition. In this capacity, pet dogs can serve as valuable corroborative models for realizing the science and best clinical practices necessary for understanding and combating osteosarcoma metastases.

Project description:PurposeAccurate verification of tumor position during irradiation could reduce the probability of target miss. We investigated whether a commercial gantry-mounted 2-dimensional (2D) kilo-voltage (kV) imaging system could be used for real-time 3D tumor tracking during volumetric modulated arc therapy (VMAT) lung stereotactic body radiation therapy (SBRT). Markerless tumor tracking on kV fluoroscopic images was validated using a life-like moving thorax phantom and subsequently performed on kV images continuously acquired before and during free-breathing VMAT lung SBRT.Methods and materialsThe 3D-printed/molded phantom containing 3 lung tumors was moved in 3D in TrueBeam developer mode, using simulated regular/irregular breathing patterns. Planar kV images were acquired at 7 frames/s during 11 Gy/fraction 10 MV flattening filter free VMAT. 2D reference templates were created for each gantry angle using the planning 4D computed tomography inspiration phase. kV images and templates were matched using normalized cross correlation to determine 2D tumor position, and triangulation of 2D matched projections determined the third dimension. 3D target tracking performed on cone beam computed tomography projection data from 18 patients (20 tumors) and real-time online tracking data from 2 of the 18 patients who underwent free-breathing VMAT lung SBRT are presented.ResultsFor target 1 and 2 of the phantom (upper lung and middle/medial lung, mean density -130 Hounsfield units), 3D results within 2 mm of the known position were present in 92% and 96% of the kV projections, respectively. For target 3 (inferior lung, mean density -478 Hounsfield units) this dropped to 80%. Benchmarking against the respiratory signal, 13/20 (65%) tumors (10.5 ± 11.1 cm3) were considered successfully tracked on the cone beam computed tomography data. Tracking was less successful (≤50% of the time) in 7/20 (1.2 ± 1.5 cm3). Successful online tracking during lung SBRT was demonstrated.Conclusions3D markerless tumor tracking on a standard linear accelerator using template matching and triangulation of free-breathing kV fluoroscopic images was possible in 65% of small lung tumors. The smallest tumors were most challenging.

Dataset Information

Modeling metastasis biology and therapy in real time in the mouse lung.

Publications

Modeling metastasis biology and therapy in real time in the mouse lung.

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