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. 2010 Mar;101(3):751-8.
doi: 10.1111/j.1349-7006.2009.01426.x. Epub 2009 Nov 6.

Lactobacillus rhamnosus GG induces tumor regression in mice bearing orthotopic bladder tumors

Shih Wee Seow  1 , Shirong Cai, Juwita N Rahmat, Boon Huat Bay, Yuan Kun Lee, Yiong Huak Chan, Ratha Mahendran
Affiliations

Lactobacillus rhamnosus GG induces tumor regression in mice bearing orthotopic bladder tumors

Shih Wee Seow et al. Cancer Sci. 2010 Mar.

Abstract

The present gold standard for bladder cancer is Mycobacterium bovis, Bacillus Calmette Guerin (BCG) immunotherapy. But it has a non-responder rate of 30-50% and side effects are common. Lactobacillus casei strain Shirota has been reported to reduce the incidence of recurrence in bladder cancer patients and to cure tumor-bearing mice. Our aim was to determine if Lactobacillus rhamnosus GG (LGG) could be as efficacious as BCG in a murine model of bladder cancer. MB49 bladder cancer cells secreting human prostate-specific antigen were implanted orthotopically in female C57BL/6 mice and urinary prostate-specific antigen levels were used as a marker of tumor growth. Mice were treated with either live or lyophilized LGG given via intravesical instillation, or both oral and intravesical LGG given once a week for a period of 6 weeks starting at day 4 after tumor implantation. A comparison of LGG and BCG immunotherapy was also carried out. LGG therapy (live or lyophilized) significantly (P = 0.006) increased the number of cured mice. Cytokine arrays and immune cell recruitment analysis revealed differences between untreated, treated, cured, and tumor-bearing mice. LGG therapy restored XCL1 levels to those in healthy bladders. LGG also recruited large numbers of neutrophils and macrophages to the tumor site. Intravesical LGG and BCG immunotherapy had cure rates of 89 and 77%, respectively, compared with 20% in untreated mice. LGG has the potential to replace BCG immunotherapy for the treatment of bladder cancer.

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Figures

Figure 1
Figure 1
X‐ray images of antibody arrays. The 96 proteins analyzed were distributed between two arrays: (A) array 4.1, containing antibodies to 34 proteins and (B) array 3.1, containing antibodies to 62 proteins. Each antibody was represented by two spots on the array. The three panels from left to right are the arrays probed with bladder protein homogenates from control PBS‐treated mice still bearing tumors, and lyophilized (Lyo) Lactobacillus rhamnosus GG (LGG)‐treated mice that were tumor‐bearing and Lyo LGG‐treated mice that were cured at the time of termination of the experiment. Proteins expressed in tumor‐bearing mice treated with LGG with a twofold difference with respect to the control tumor‐bearing mice are identified by having their relative position on the arrays circled in white and labeled. The proteins are thymus chemokine 1 (CK), vascular endothelial growth factor (VEGF), osteopontin (OPN), inter‐cellular adhesion molecule 1 (ICAM‐1), macrophage inflammatory protein (MIP), soluble tumor necrosis factor receptor inhibitor I (sTNFRII), interleukin (IL), vascular cell adhesion molecule 1 (VCAM‐1), LPS induced C‐X‐C chemokine (LIX) and platelet factor (PF).
Figure 2
Figure 2
Bladder tumor sections were examined by immunohistochemistry. The photos show (A) a mouse bladder with a tumor indicated by the arrow (20x magnification), (B) infiltrating immune cells after lyophilized (Lyo) Lactobacillus rhamnosus GG (LGG) treatment (600× magnification), the arrow indicates bi‐lobed neutrophils. Mac‐3+ cells (stained brown) in (C) control tumors and (D) lyo LGG‐treated tumors (400× magnification) with arrows indicating the macrophage cells. Neutrophils (stained brown) in (E,G) control and (F,H) Lyo LGG‐treated tumors at (E,F) low magnification (40× magnification) and (G,H) high magnification (400× magnification of boxed regions in E,F). There were consistently more neutrophils within tumors of Lyo LGG mice than control mice when samples were examined under 400× magnification.
Figure 3
Figure 3
Cytokine production by neutrophils cultured with Lactobacillus rhamnosus GG (LGG) and Mycobacterium bovis, Bacillus Calmette Guerin (BCG). The production of (A) tumor necrosis factor (TNFα) and (B) interleukin (IL‐10) by neutrophils after 2 and 18 h of exposure to LGG or BCG, at a bacteria to neutrophil ratio of 5:1. The supernatant of the 2‐h treatment group was collected 18 h after killing off the extracellular bacteria and replacement with fresh media and this was therefore comparable to the 18‐h treatment group. Data are presented as the mean ± SEM. *Statistical significance (P < 0.05) from untreated control.
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