title: Motility is critical for effective distribution and accumulation of bacteria in tumor tissue.
abstract: Motile bacteria can overcome the penetration limitations of cancer chemotherapeutics because they can actively migrate into solid tumors. Although several genera of bacteria have been shown to accumulate preferentially in tumors, the spatiotemporal dynamics of bacterial tumor colonization and their dependence on bacterial motility are not clear. For effective tumor regression, bacteria must penetrate and distribute uniformly throughout tumors. To measure these dynamics, we used an in vitro model of continuously perfused tumor tissue to mimic the delivery and systemic clearance of Salmonella typhimurium strains SL1344 and VNP20009, and Escherichia coli strains K12 and DH5α. Tissues were treated for 1 hour with 10(5) or 10(7) CFU ml(-1) suspensions of each strain and the location and extent of bacterial accumulation were observed for 30 hours. Salmonella had 14.5 times greater average swimming speed than E. coli and colonized tissues at 100 times lower doses than E. coli. Bacterial motility strongly correlated (R(2) = 99.3%) with the extent of tissue accumulation. When inoculated at 10(5) CFU ml(-1), motile Salmonella formed colonies denser than 10(10) CFU/(g-tissue) and less motile E. coli showed no detectable colonization. Based on spatiotemporal profiles and a mathematical model of motility and growth, bacterial dispersion was found to be necessary for deep penetration into tissue. Bacterial colonization caused apoptosis in tumors and apoptosis levels correlated (R(2) = 98.6%) with colonization density. These results show that motility is critical for effective distribution of bacteria in tumors and is essential for designing cancer therapies that can overcome the barrier of limited tumor penetration.
authors.affiliation: 159 Goessman Laboratory, Department of Chemical Engineering, University of Massachusetts, Amherst, 686 North Pleasant Street, Amherst, MA 01003-9303, USA.
authors.forename: Bhushan J
authors.initials: BJ
authors.lastname: Toley
authors.forename: Neil S
authors.initials: NS
authors.lastname: Forbes
mesh_terms: D000230:Adenocarcinoma / Q000098:blood supply / Q000382:microbiology* / Q000473:pathology; D017209:Apoptosis / Q000502:physiology; D045744:Cell Line, Tumor; D015169:Colony Count, Microbial; D015179:Colorectal Neoplasms / Q000098:blood supply / Q000382:microbiology* / Q000473:pathology; D004926:Escherichia coli / Q000254:growth & development*; D006801:Humans; D046210:Microfluidic Analytical Techniques; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D009389:Neovascularization, Pathologic / Q000382:microbiology / Q000473:pathology; D012480:Salmonella Infections / Q000150:complications* / Q000382:microbiology / Q000473:pathology; D012486:Salmonella typhimurium / Q000254:growth & development*