TEMTIA V ~ October 10-13, 2011 in Singapore
The Solid Tumor Microenvironment: Potential Selective Therapeutic Target of Anti-Oxidant Activities that Block Tumor Progression
Authors : Sarah Crawford, PhD Deanna Diamond Rafaela Penarreta Holly Schurk
Affiliations : Cancer Biology Research Laboratory Southern Connecticut State University
Presenting author : Sarah Crawford, PhD
Email address : crawfords2@southernct.edu
Contact number :
Award Applied : TEMTIA Travel Bursary
Member of American Association of Anatomists : Not Applicable
Abstract text : Increasing evidence suggests a potential benefit of anti-oxidants not only in the prevention but also the treatment of cancer. The physiological basis for this therapeutic benefit may derive from the unique biological parameters that define the microenvironment generated by solid tumors. Tumor micro-environmental components that drive cancer progression include: hypoxic interior associated with oxidative stress responses, inflammatory pathways critical to tumor survival, glycolysis and altered redox regulation of cell growth, altered biophysical parameters of growth regulation associated with increased tumor vesicle production. Each of these parameters is essential to tumor progression and by definition represents a potential therapeutic target. The central thesis of this research is that anti-oxidant activities should disable the primary physiological aberrations associated with tumor progression and this may explain their observed preventive effects on cancer development and may also provide the foundation for the development of a novel class of cancer therapeutics whose primary biological effects are associated with anti-oxidant activity. The model for the environmental impact on solid tumor biology involves the proposed sequence of events which can be correlated to the classic initiation/ promotion/ progression model of tumorigenesis at the level of solid tumor biology: · Hyperplastic growth associated with proliferative dysregulation results in disorganized tissue structural organization that affects tissue polarity and cell contact/attachment parameters. · Tissue disorganization promotes solid tumor formation by abrogating normal cell contact attachment parameters that produce epigenetic effects on cell signal/transcription processes that contribute to EMT of affected tissue. · Cytoarchitectural disruption increases the production of TAMVs that elicit morphological transformation of stromal tissue by a processs the lab has termed “insertional membrane editing”. These changes further promote the formation of incipient solid tumors in situ, whose formation is in part mediated by extracellualar TAMVs. The formation of solid tumors exerts a profound effect on the local microenvironment particularly in the interior layers of the tumor in which poor vascularization induces hypoxia and extensive genetic reprogramming of affected tissue. This is associated with oxidative stress, altered redox state, increased glycolysis, and acidification, all of which contribute to tumor progression to systemic disease. Among these tumor progression factors are the switch to a genetic program that is pro-inflammatory, anti-apoptotic and characterized by enhanced invasiveness and increased cell motility. What is the proposed mechanism by which anti-oxidants may derail these abnormal processes that contribute to tumor progression? • Altered redox state facilitating aerobic oxidative phosphorylation associated with decreased reliance on glycolysis as the sole source of energy production. • Interference with hypoxia associated oxidative damage that contributes the activities of survival pathways such as HIF-1 alpha and NFkB. The absence of these pro-survival mechanisms causes the death of non-dividing tumor cells at the interior core that drive tumor progression. Research data on solid tumor microenvironmental parameters from our laboratory have shown the following: · Serum depletion +/- elevated glucose is associated with substrate detachment and spontaneous cell clustering to form spheroids · Co-cultivation of cell-free tumor associated microvesicles (TAMVs) and non-transformed diploid fibroblast cells induces morphological transformation. · Increased extracellular Ca++ is associated with increased TAMV production and altered tumor morphology · Anti-oxidant plant –derived phenolic compounds display selective cytotoxicity on solid tumor spheroids versus monolayer substrate attached cultures (normal or transformed). · Dose/response assays were performed on tumor spheroids from established human cancer cell lines of the breast, colon, lung brain and osteosarcoma. Assays consisted of cell cytotoxicity with IC50 determinations, tumor cell re-growth and post-treatment survival. · Selective cytotoxicity was observed in tumor spheroids from diverse cancers compared to monolayer tumor cultures or normal fibroblasts. Complete tumor killing occurred at about 100 microgram per mL · Combined cytotoxicity was observed with cisplatin, fluorouracil and paclitaxel. These pre-clinical findings are supported by clinical trials asserting a therapeutic benefit of anti-oxidant use in prolonging remission and reducing recurrence rates of important cancers.
