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 is 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 105 or 107 CFU/ml suspensions of each strain and the location and extent of bacterial accumulation was observed for 30 hours. Salmonella had 14.5 times greater average swimming speeds than E.coli and colonized tissues at 100 times lower doses than E.coli. Bacterial motility strongly correlated (R2 = 99.3%) with the extent of tissue accumulation. When inoculated at 105 CFU/ml, motile Salmonella formed colonies denser than 1010 CFU/(g-tissue) and less motile E.coli showed no detectable colonization. Based on spatio-temporal 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 (R2 = 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.

Engineered bacteria as therapeutic agents

“…These include enhanced bacterial entry and retention in tumors caused by their chaotic and leaky vasculature [22,23] and unimpeded bacterial replication in the anoxic and immunedeficient tumor microenvironment, which lacks macrophage and neutrophil clearance mechanisms [24]. Chemotaxis and active motility of bacteria has also been shown to have a positive influence in the colonization of tumors [25,26]. Intra-vesicle administration of Bacillus Calmé tte-Guerin (BCG) has been used in the clinic during the last decades as the standard treatment for high-grade non-muscle invasive bladder cancer [27], representing a good example of a current anti-cancer therapy in which bacteria is employed to stimulate the immune system in order to promote the killing of cancer cells by a mechanism that is not yet fully understood.…”

Salmonella-Mediated Cancer Therapy: Roles and Potential

“…The tumortargeting mechanism of facultative bacteria is complex and is the subject of debate. Generally, there are two opposing theories to explain this mechanism: (1) the chemotactic system and motility of bacteria mediate the successful bacterial colonization of tumors [45][46][47], and (2) a passive mechanism by which inflammatory cytokines are triggered after intravenous injection of bacteria leads to the dilation of tumor blood vessels, allowing the entry of bacteria [48,49]. Work from our group using non-motile Salmonella with a mutation in the flhD gene showed that they accumulate in tumors to an extent comparable to that of motile bacteria (unpublished data).…”

Quorum-sensing Salmonella selectively trigger protein expression within tumors

“…Administration of QS Salmonella with exogenous lipid A (12) and enhanced motility (12,38) would increase bacterial density and improve distribution within tumors. Combined, these effects could increase density 253-fold and increase overall drug production.…”