title: Subclinical photodynamic therapy treatment modifies the brain microenvironment and promotes glioma growth.
abstract: Photodynamic therapy (PDT) has been clinically investigated as an adjuvant local therapy for brain tumors. Therapeutic interventions intended to promote tumor cell death can also promote changes in the tumor microenvironment that could favor tumor growth. We have previously shown that PDT can activate pro-angiogenic factors in the normal rodent brain. This study seeks to further elucidate the effects of subtherapeutic doses of Photofrin-PDT on normal brain and to establish a mouse model for studying glioma progression in an environment modified by oxidative stress. Photofrin was administered to nude mice, and a defined intracranial area was illuminated with laser to deliver an optical dose equivalent to 80 J/cm(2). Three and 7 days after PDT, mice were sacrificed and brains were fixed and analyzed by immunohistochemistry. PDT treatment resulted in transient increase in cell proliferation, associated with a robust activation of astrocytes and microglia in the treated region, without causing substantial cell death. To test how this modified environment would affect glioma growth, human glioblastoma U87 cells were implanted in the PDT-treated hemisphere or in the control brain subjected to sham surgery. Significantly larger tumors were observed after 3 weeks in the PDT treated brains relative to control treatment. Our results indicate that subclinical Photofrin-PDT locally alters the brain homeostasis without inflicting significant disruption to the tissue architecture, providing a model to study the effects of the microenvironment on glioma growth, with implications for the optimization of the clinical use of PDT for brain tumors.
authors.affiliation: Departments of Neurology, Henry Ford Health Sciences Center, Detroit, Michigan, USA.
authors.forename: Ana C
authors.initials: AC
authors.lastname: deCarvalho
authors.forename: Xuepeng
authors.initials: X
authors.lastname: Zhang
authors.forename: Cynthia
authors.initials: C
authors.lastname: Roberts
authors.forename: Feng
authors.initials: F
authors.lastname: Jiang
authors.forename: Steven N
authors.initials: SN
authors.lastname: Kalkanis
authors.forename: Xin
authors.initials: X
authors.lastname: Hong
authors.forename: Mei
authors.initials: M
authors.lastname: Lu
authors.forename: Michael
authors.initials: M
authors.lastname: Chopp
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects; D014408:Biomarkers, Tumor / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D016923:Cell Death / Q000187:drug effects / Q000528:radiation effects; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D017323:Dihematoporphyrin Ether / Q000009:adverse effects*; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D005911:Gliosis / Q000139:chemically induced / Q000503:physiopathology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D009457:Neuroglia / Q000187:drug effects / Q000528:radiation effects; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010775:Photic Stimulation / Q000009:adverse effects / Q000379:methods; D010778:Photochemotherapy / Q000009:adverse effects* / Q000379:methods / Q000592:standards; D017211:Treatment Failure
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D017323:Dihematoporphyrin Ether