Bacteria as vectors for gene therapy of cancer

Baban, Chwanrow; Cronin, Michelle; O’Hanlon, Deirdre; O’Sullivan, Gerald C.; Tangney, Mark

doi:10.4161/bbug.1.6.13146

Cited by 157 publications

(109 citation statements)

References 119 publications

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“…Preclinical studies have shown the ability of different bacterial strains to locally produce therapeutic agents and mediate highly effective and specific therapeutic responses. 5 A wide range of gene therapy strategies exists, aiming at inducing malignant cell death either directly (e.g. using 'suicide' genes) or indirectly, such as cancer immunotherapy approaches based on killing tumor cells through intervention of various effector cells of the immune system.…”

Section: Bacterial-mediated Tumor Therapymentioning

confidence: 99%

“…51 However, the employment of luciferase or lux tagged bacterial strains as gene delivery vehicles for the treatment of cancer is an emerging field. 52,53 A powerful potential diagnostic approach involves the use of genetically modified light-emitting bacteria to visualize their colonization of tumors (Figure 3), thereby revealing the location of tumors based on light emission.…”

Section: Bioluminescence Imaging (Bli)mentioning

confidence: 99%

“…5 The tumor selective growth of bacteria has made them an attractive vehicle for the delivery of reporter genes, therapeutic genes or inhibitory RNA to a tumor for ameliorative or potentially diagnostic purposes. Protocols for the genetic modification of bacterial genomes and the transformation of plasmid DNA containing genes of interest into bacteria are becoming established for an increasing range of species.…”

Section: Introductionmentioning

confidence: 99%

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Bacterial vectors for imaging and cancer gene therapy: a review

et al. 2012

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The significant burden of resistance to conventional anticancer treatments in patients with advanced disease has prompted the need to explore alternative therapeutic strategies. The challenge for oncology researchers is to identify a therapy which is selective for tumors with limited toxicity to normal tissue. Engineered bacteria have the unique potential to overcome traditional therapies' limitations by specifically targeting tumors. It has been shown that bacteria are naturally capable of homing to tumors when systemically administered resulting in high levels of replication locally, either external to (non-invasive species) or within tumor cells (pathogens). Pre-clinical and clinical investigations involving bacterial vectors require relevant means of monitoring vector trafficking and levels over time, and development of bacterial-specific real-time imaging modalities are key for successful development of clinical bacterial gene delivery. This review discusses the currently available imaging technologies and the progress to date exploiting these for monitoring of bacterial gene delivery in vivo.Cancer Gene Therapy ( INTRODUCTIONAlthough the potential anti-cancer effects of acquired bacterial infection have been evident for over 120 years and the presence of bacteria in excised tumors has been noted for over 60 years, 1 it is only in more recent times that the tumor-specific growth of bacteria has been considered for therapeutic purposes. While the precise mechanism(s) behind preferential bacterial tumor colonization remain poorly understood, this phenomenon must relate to unique tumor attributes that separate them from healthy tissues. Factors such as the irregular blood supply; local immune suppression; inflammation; and unique nutrient supply (e.g., purines) in tumors have been proposed to play a role. 2 Bacterial entry into the tumor environment is proposed to be facilitated by the leaky vasculature. Cancer cells are characterized by an aberrantly accelerated metabolism and proliferation leading to an imbalance of oxygen supply and consumption which is a major causative factor of tumor hypoxia. 3 The hypoxic nature of solid tumors enhances the growth of anaerobic and facultatively anaerobic bacteria. In addition, these areas with low oxygen and high interstitial pressure are considered to be an immunological sanctuary, where bacterial clearance mechanisms are greatly inhibited. 4 Necrotic regions are also rich in nutrients favoured by bacteria due to tumor cell turnover. However, tumor selective bacterial colonization now appears to be both bacterial species and tumor origin independent, since aerobic bacteria are also capable of colonising tumors, and even small tumors lacking an anaerobic center are colonised. See Figure 1 for proposed mechanisms.Invasive bacteria can internalize and replicate within tumor cells, while non-invasive bacteria grow externally to tumor cells, within the tumor micro-environment. 5 The tumor selective growth of bacteria has made them an attractive vehicle for the delivery of ...

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Section: Bacterial-mediated Tumor Therapymentioning

confidence: 99%

Section: Bioluminescence Imaging (Bli)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Bacterial vectors for imaging and cancer gene therapy: a review

et al. 2012

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“…Murine models of spontaneously arising tumors more closely resemble clinical reality in terms of vasculature (a potential variable in bacterial colonization of tumors), and bacteria have also been shown to colonize such models 6 . Various preclinical and clinical trials have shown the ability of different bacterial strains to transport and amplify genes encoding factors such as prodrug-converting enzymes, toxins, angiogenesis inhibitors, and cytokines specifically within tumors 4,7 . While bacterial tumor colonization has been shown to be independent of bacterial strain and tumor type 6 , the choice of strain optimal for a particular model may vary -e.g.…”

Section: Discussionmentioning

confidence: 99%

Bioluminescent Bacterial Imaging <em>In Vivo</em>

Baban

Cronin

Akin

et al. 2012

JoVE

Self Cite

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This video describes the use of whole body bioluminesce imaging (BLI) for the study of bacterial trafficking in live mice, with an emphasis on the use of bacteria in gene and cell therapy for cancer. Bacteria present an attractive class of vector for cancer therapy, possessing a natural ability to grow preferentially within tumors following systemic administration. Bacteria engineered to express the lux gene cassette permit BLI detection of the bacteria and concurrently tumor sites. The location and levels of bacteria within tumors over time can be readily examined, visualized in two or three dimensions. The method is applicable to a wide range of bacterial species and tumor xenograft types. This article describes the protocol for analysis of bioluminescent bacteria within subcutaneous tumor bearing mice. Visualization of commensal bacteria in the Gastrointestinal tract (GIT) by BLI is also described. This powerful, and cheap, real-time imaging strategy represents an ideal method for the study of bacteria in vivo in the context of cancer research, in particular gene therapy, and infectious disease. This video outlines the procedure for studying lux-tagged E. coli in live mice, demonstrating the spatial and temporal readout achievable utilizing BLI with the IVIS system. Video LinkThe video component of this article can be found at http://www.jove.com/video/4318/ Protocol 1. Tumor Induction 1. For routine tumor induction, the minimum tumorigenic dose of cells suspended in 200 μl of serum-free culture medium was injected subcutaneously (s.c.) into the flank of infection free 6-8 week old female Balb/C or athymic MF1-nu/nu mice n=6 (Harlan, Oxfordshire, UK) (1 x 10 6 4T1 cells) using a 21-gauge syringe needle. The viability of cells used for inoculation was greater than 95 % as determined by visual count using a haemocytometer and Trypan Blue Dye Exclusion (Gibco). 2. Following tumor establishment, tumors were allowed to grow and develop and were monitored twice weekly. Tumor volume was calculated according to the formula V=(ab 2 ) Π/6, where a is the longest diameter of the tumor and b is the longest diameter perpendicular to diameter a.

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“…More significantly, bacteria can grow selectively in disease tissue thereby compensating for poor targeting [21]. Bacteria have been used to deliver anti-cancer drugs or nanoparticles and to deliver genes intracellular [22,23]. Successful tumor regression studies in mice [24] and other laboratory animals have led to recent FDA approved clinical trials of bacterial targeted anti cancer treatments [25][26][27].…”

Section: Introductionmentioning

confidence: 99%

Factors Affecting Bacterial Propagation towards Tumor Microenvironments

Koduvayur¹

2016

MOJPB

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This paper provides a detailed analysis to identify factors that improve bacterial targeting times to tumor microenvironments. We utilize the "active flagellar" motion characteristic of the bacterial movement to present a continuous time Markov model and a first passage time analysis to determine the factors that affect the mean time taken for injected bacteria to reach a tumor micro environment. We have determined 3 major factors that play a role in determining mean targeting times: (i) the population of the injected bacteria, (ii) the distance between the region of injection and the tumor microenvironment and (iii) the directional efficiency of the injected bacteria. Of these 3 factors our results show that the directional efficiency is the most significant factor that affects the time taken by different bacterial species to reach the tumor micro environment. While distance between the tumor micro environment and the region of injection also plays an important role, population of bacteria is most ineffective, especially for large directional efficiency. Our model matches well with some existing experimental results.

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Bacteria as vectors for gene therapy of cancer

Cited by 157 publications

References 119 publications

Bacterial vectors for imaging and cancer gene therapy: a review

Bacterial vectors for imaging and cancer gene therapy: a review

Bioluminescent Bacterial Imaging <em>In Vivo</em>

Factors Affecting Bacterial Propagation towards Tumor Microenvironments

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