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Betulinic acid impairs metastasis and reduces immunosuppressive cells in breast cancer models.

ABSTRACT: Breast cancer is the most common female cancer with considerable metastatic potential, explaining the need for new candidates that inhibit tumor metastasis. In our study, betulinic acid (BA), a kind of pentacyclic triterpenoid compound derived from birch trees, was evaluated for its anti-metastasis activity in vitro and in vivo. BA decreased the viability of three breast cancer cell lines and markedly impaired cell migration and invasion. In addition, BA could inhibit the activation of stat3 and FAK which resulted in a reduction of matrix metalloproteinases (MMPs), and increase of the MMPs inhibitor (TIMP-2) expression. Moreover, in our animal experiment, intraperitoneal administration of 10 mg/kg/day BA suppressed 4T1 tumor growth and blocked formation of pulmonary metastases without obvious side effects. Furthermore, histological and immunohistochemical analyses showed a decrease in MMP-9 positive cells, MMP-2 positive cells and Ki-67 positive cells and an increase in cleaved caspase-3 positive cells upon BA administration. Notably, BA reduced the number of myeloid-derived suppressor cells (MDSCs) in the lungs and tumors. Interestingly, in our caudal vein model, BA also obviously suppressed 4T1 tumor pulmonary metastases. These findings suggested that BA might be a potential agent for inhibiting the growth and metastasis of breast cancer.

SUBMITTER: Zeng AQ

PROVIDER: S-EPMC5790500 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Betulinic acid impairs metastasis and reduces immunosuppressive cells in breast cancer models.

Zeng An-Qi AQ Yu Yan Y Yao Yu-Qin YQ Yang Fang-Fang FF Liao Mengya M Song Lin-Jiang LJ Li Ya-Li YL Yu Yang Y Li Yu-Jue YJ Deng Yuan-Le YL Yang Shu-Ping SP Zeng Chen-Juan CJ Liu Ping P Xie Yong-Mei YM Yang Jin-Liang JL Zhang Yi-Wen YW Ye Ting-Hong TH Wei Yu-Quan YQ

Oncotarget 20171217 3

Breast cancer is the most common female cancer with considerable metastatic potential, explaining the need for new candidates that inhibit tumor metastasis. In our study, betulinic acid (BA), a kind of pentacyclic triterpenoid compound derived from birch trees, was evaluated for its anti-metastasis activity <i>in vitro</i> and <i>in vivo</i>. BA decreased the viability of three breast cancer cell lines and markedly impaired cell migration and invasion. In addition, BA could inhibit the activatio ...[more]

PMID: 29423083

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Project description:Increased expression of ?v integrins is frequently associated with tumor cell adhesion, migration, invasion and metastasis, and correlates with poor prognosis in breast cancer. However, the mechanism by which ?v integrins can enhance breast cancer progression is still largely unclear. The effects of therapeutic targeting of ?v integrins in breast cancer also have yet to be investigated.We knocked down ?v integrin in MDA-MB-231 and MCF10A-M4 breast cancer cells, or treated these cells with the ?v antagonist GLPG0187. The effects of ?v integrin depletion on mesenchymal markers, transforming growth factor-? (TGF-?)/Smad signaling and TGF-?-induced target gene expression were analyzed in MDA-MB-231 cells by RNA analysis or Western blotting. The function of ?v integrin on breast cancer cell migration was investigated by transwell assay in vitro, and its effect on breast cancer progression was assessed by both zebrafish and mouse xenografts in vivo. In the mouse model, GLPG0187 was administered separately, or in combination with the standard-of-care anti-resorptive agent zoledronate and the chemotherapeutic drug paclitaxel, to study the effects of combinational treatments on breast cancer metastasis.Genetic interference and pharmacological targeting of ?v integrin with GLPG0187 in different breast cancer cell lines inhibited invasion and metastasis in the zebrafish or mouse xenograft model. Depletion of ?v integrin in MDA-MB-231 cells inhibited the expression of mesenchymal markers and the TGF-?/Smad response. TGF-? induced ?v integrin mRNA expression and ?v integrin was required for TGF-?-induced breast cancer cell migration. Moreover, treatment of MDA-MB-231 cells with non-peptide RGD antagonist GLPG0187 decreased TGF-? signaling. In the mouse xenografts GLPG0187 inhibited the progression of bone metastasis. Maximum efficacy of inhibition of bone metastasis was achieved when GLPG0187 was combined with the standard-of-care metastatic breast cancer treatments.These findings show that ?v integrin is required for efficient TGF-?/Smad signaling and TGF-?-induced breast cancer cell migration, and for maintaining a mesenchymal phenotype of the breast cancer cells. Our results also provide evidence that targeting ?v integrin could be an effective therapeutic approach for treatment of breast cancer tumors and/or metastases that overexpress ?v integrin.

Project description:BackgroundThe upregulation of antioxidant mechanisms is a common occurrence in cancer cells, as they strive to maintain balanced redox state and prevent oxidative damage. This includes the upregulation of the cystine/glutamate antiporter xCT, which plays a crucial role in protecting cancer cells from oxidative stress. Consequently, targeting xCT has become an attractive strategy for cancer treatment. However, xCT is also expressed by several types of immune cells where it has a role in proliferation and effector functions. In light of these observations, a comprehensive understanding of the specific role of xCT in the initiation and progression of cancer, as well as its potential impact on the immune system within the tumor microenvironment and the anti-tumor response, require further investigation.MethodsWe generated xCTnull BALB/c mice to investigate the role of xCT in the immune system and xCTnull/Erbb2-transgenic BALB-neuT mice to study the role of xCT in a mammary cancer-prone model. We also used mammary cancer cells derived from BALB-neuT/xCTnull mice and xCTKO 4T1 cells to test the contribution of xCT to malignant properties in vitro and in vivo.ResultsxCT depletion in BALB-neuT/xCTnull mice does not alter autochthonous tumor initiation, but tumor cells isolated from these mice display proliferation and redox balance defects in vitro. Although xCT disruption sensitizes 4T1 cells to oxidative stress, it does not prevent transplantable tumor growth, but reduces cell migration in vitro and lung metastasis in vivo. This is accompanied by an altered immune cell recruitment in the pre-metastatic niche. Finally, systemic depletion of xCT in host mice does not affect transplantable tumor growth and metastasis nor impair the proper mounting of both humoral and cellular immune responses in vivo.ConclusionsxCT is dispensable for proper immune system function, thus supporting the safety of xCT targeting in oncology. Nevertheless, xCT is involved in several processes required for the metastatic seeding of mammary cancer cells, thus broadening the scope of xCT-targeting approaches.

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Betulinic acid impairs metastasis and reduces immunosuppressive cells in breast cancer models.

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Betulinic acid impairs metastasis and reduces immunosuppressive cells in breast cancer models.

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