CXCR2: A Novel Mediator of Mammary Tumor Bone Metastasis

Most breast cancer patients die due to bone metastasis. Although metastasis accounts for 5% of the breast cancer cases, it is responsible for most of the deaths. Sometimes even before the detection of a primary tumor, most of the patients have bone and lymph node metastasis. Moreover, at the time of death, breast cancer patients have the bulk of the tumor burden in their bones. Therapy options are available for the treatment of primary tumors, but there are minimal options for treating breast cancer patients who have bone metastasis. C-X-C motif chemokine receptor type 2 (CXCR2) receptor-mediated signaling has been shown to play a critical role during bone-related inflammations and its ligands C-X-C motif chemokine ligand 6 (CXCL6) and 8 (CXCL8) aid in the resorption of bone during bone metastasis. In this study, we tested the hypothesis that CXCR2 contributes to mammary tumor-induced osteolysis and bone metastasis. In the present study, we examined the role of both tumor cell-derived and host-derived CXCR2 in influencing mammary tumor cell bone metastasis. For understanding the role of tumor cell-derived CXCR2, we utilized Cl66 CXCR2 knockdown (Cl66-shCXCR2) and Cl66-Control cells (Cl66-Control) and observed a significant decrease in tumor growth and tumor-induced osteolysis in Cl66-shCXCR2 cells in comparison with the Cl66-Control cells. Next, for understanding the role of host-derived CXCR2, we utilized mice with genomic knockdown of CXCR2 (Cxcr2−/−) and injected Cl66-Luciferase (Cl66-Luc) or 4T1-Luciferase (4T1-Luc) cells. We observed decreased bone destruction and metastasis in the bone of Cxcr2−/− mice. Our data suggest the importance of both tumor cell- and host-derived CXCR2 signaling in the bone metastasis of breast cancer cells.

Download Full-text

Integrin alpha5 in human breast cancer is a mediator of bone metastasis and a therapeutic target for the treatment of osteolytic lesions

Oncogene ◽

10.1038/s41388-020-01603-6 ◽

2021 ◽

Author(s):

Francesco Pantano ◽

Martine Croset ◽

Keltouma Driouch ◽

Natalia Bednarz-Knoll ◽

Michele Iuliani ◽

...

Keyword(s):

Breast Cancer ◽

Bone Marrow ◽

Bone Metastasis ◽

Tumor Cell ◽

Cancer Patients ◽

Breast Cancer Patients ◽

Osteolytic Lesions ◽

Cell Colonization

AbstractBone metastasis remains a major cause of mortality and morbidity in breast cancer. Therefore, there is an urgent need to better select high-risk patients in order to adapt patient’s treatment and prevent bone recurrence. Here, we found that integrin alpha5 (ITGA5) was highly expressed in bone metastases, compared to lung, liver, or brain metastases. High ITGA5 expression in primary tumors correlated with the presence of disseminated tumor cells in bone marrow aspirates from early stage breast cancer patients (n = 268; p = 0.039). ITGA5 was also predictive of poor bone metastasis-free survival in two separate clinical data sets (n = 855, HR = 1.36, p = 0.018 and n = 427, HR = 1.62, p = 0.024). This prognostic value remained significant in multivariate analysis (p = 0.028). Experimentally, ITGA5 silencing impaired tumor cell adhesion to fibronectin, migration, and survival. ITGA5 silencing also reduced tumor cell colonization of the bone marrow and formation of osteolytic lesions in vivo. Conversely, ITGA5 overexpression promoted bone metastasis. Pharmacological inhibition of ITGA5 with humanized monoclonal antibody M200 (volociximab) recapitulated inhibitory effects of ITGA5 silencing on tumor cell functions in vitro and tumor cell colonization of the bone marrow in vivo. M200 also markedly reduced tumor outgrowth in experimental models of bone metastasis or tumorigenesis, and blunted cancer-associated bone destruction. ITGA5 was not only expressed by tumor cells but also osteoclasts. In this respect, M200 decreased human osteoclast-mediated bone resorption in vitro. Overall, this study identifies ITGA5 as a mediator of breast-to-bone metastasis and raises the possibility that volociximab/M200 could be repurposed for the treatment of ITGA5-positive breast cancer patients with bone metastases.

Download Full-text

The Critical Role of Axillary Ultrasound and Aspiration Biopsy in the Management of Breast Cancer Patients with Clinically Negative Axilla

Annals of Surgical Oncology ◽

10.1245/s10434-007-9524-3 ◽

2007 ◽

Vol 15 (1) ◽

pp. 250-255 ◽

Cited By ~ 29

Author(s):

J. L. Hinson ◽

P. McGrath ◽

A. Moore ◽

J. T. Davis ◽

Y. M. Brill ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Critical Role ◽

Aspiration Biopsy ◽

Breast Cancer Patients ◽

Axillary Ultrasound

Download Full-text

Bisphosphonates and metastasis

Breast Cancer Online ◽

10.1017/s1470903104002676 ◽

2005 ◽

Vol 8 (1) ◽

Author(s):

J. Lester ◽

R. Coleman

Keyword(s):

Breast Cancer ◽

Bone Metastasis ◽

Cancer Patients ◽

Breast Cancer Patients ◽

Control Pain ◽

High Risk Breast Cancer ◽

High Risk Breast ◽

Risk Breast Cancer ◽

Bone Physiology

Bone metastases frequently occur in advanced breast cancer patients and once incorporated into bone have profound effects on bone physiology. Bisphosphonates are potent inhibitors of osteoclastic function and are becoming increasingly important for the management of patients with breast cancer. They affect the ability of cancer cells to accelerate bone turnover and as a result control pain and reduce the risk of pathological fracture.Furthermore ongoing clinical trials are investigating the role of bisphosphonates as an adjuvant therapy in high-risk breast cancer patients with an aim to prevent bone metastasis.This article reviews the mechanisms of bone metastasis and will discuss present and future developments for the monitoring and treatment of metastatic bone disease.

Download Full-text

Role of Circulating Tumor Cell (CTC) Monitoring in Evaluating Prognosis of Triple-Negative Breast Cancer Patients in China

Medical Science Monitor ◽

10.12659/msm.902637 ◽

2017 ◽

Vol 23 ◽

pp. 3071-3079 ◽

Cited By ~ 13

Author(s):

Yanwu Zhang ◽

Yidong Lv ◽

Yaodong Niu ◽

Hongge Su ◽

Aiqiang Feng

Keyword(s):

Breast Cancer ◽

Tumor Cell ◽

Cancer Patients ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Circulating Tumor Cell ◽

Breast Cancer Patients

Download Full-text

Receptor Activator of NF-kB (RANK) Expression in Primary Tumors Associates with Bone Metastasis Occurrence in Breast Cancer Patients

PLoS ONE ◽

10.1371/journal.pone.0019234 ◽

2011 ◽

Vol 6 (4) ◽

pp. e19234 ◽

Cited By ~ 119

Author(s):

Daniele Santini ◽

Gaia Schiavon ◽

Bruno Vincenzi ◽

Laura Gaeta ◽

Francesco Pantano ◽

...

Keyword(s):

Breast Cancer ◽

Bone Metastasis ◽

Cancer Patients ◽

Breast Cancer Patients ◽

Primary Tumors ◽

Receptor Activator

Download Full-text

Hypoxia-Induced TPM2 Methylation is Associated with Chemoresistance and Poor Prognosis in Breast Cancer

Cellular Physiology and Biochemistry ◽

10.1159/000487162 ◽

2018 ◽

Vol 45 (2) ◽

pp. 692-705 ◽

Cited By ~ 15

Author(s):

Jinfeng Zhang ◽

Jian Zhang ◽

Shouping Xu ◽

Xianyu Zhang ◽

Peiyuan Wang ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Critical Role ◽

Methylation Status ◽

Matrix Metalloproteinase 2 ◽

Migration And Invasion ◽

Breast Cancer Patients ◽

Gene Target ◽

Node Metastasis

Background/Aims: Tropomyosin-2 (TPM2) plays important roles in functions of the cytoskeleton, such as cytokinesis, vesicle transport, cell proliferation, migration and apoptosis,and these functions imply that TPM2 also plays a role in cancer development. Indeed, it has been shown that TPM2 plays a critical role in some cancers. However, the role of TPM2 in breast cancer is still poorly characterized. Thus, we explored the role of TPM2 in breast cancer. Methods: We analysed TPM2 expression and its correlation with the clinicopathological features in breast cancer. Then, we examined the influence of hypoxia on TPM2 expression and methylation status using bisulfite sequencing PCR. Furthermore, we performed TPM2-mediated migration and invasion assays in the context of hypoxia and examined changes in matrix metalloproteinase-2 (MMP2) expression. Finally, we detected the influence of TPM2 on survival and chemotherapy drug sensitivity. Results: We found that TPM2 expression is down-regulated in breast cancer cells compared to that in normal breast cells. The data from TCGA supported these results. Promoter methylation of TPM2, which could be induced by hypoxia, was responsible for its low expression. Hypoxia might regulate cell invasiveness partly by TPM2 down-regulation-mediated changes of MMP2 expression. Importantly, low TPM2 expression was correlated with lymph node metastasis (P=0.031), tumour node metastasis stage (P=0.01), histological grade (P=0.037), and shorter overall survival (P=0.028). Univariate and multivariate analyses indicated that TPM2 was an independent predictor in breast cancer patients. Paclitaxel chemotherapy did not benefit patients with low TPM2 expression (P<0.0001). TPM2 knockdown significantly reduced cell sensitivity to paclitaxel. Conclusion: TPM2 is a potential novel tumour suppressor gene in breast cancer. TPM2 is associated with poor survival and chemoresistance to paclitaxel in breast cancer, and TPM2 may represent a promising therapeutic gene target for breast cancer patients with chemoresistance.

Download Full-text