CXCR3 as a molecular target in breast cancer metastasis: inhibition of tumor cell migration and promotion of host anti-tumor immunity

Zhu, Guiquan; Yan, Hannah H.; Pang, Yanli; Jiang, Jian; Achyut, Bhagelu R.; Liang, Xin‐hua; Weiss, Jonathan M.; Wiltrout, Robert H.; Hollander, M. Christine; Yang, Li

doi:10.18632/oncotarget.6125

Cited by 67 publications

(61 citation statements)

References 42 publications

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“…Metastatic engraftment of tumors, including lung metastases, has been shown to require accumulation of tumor-associated monocytes/macrophages in lung35 and tumor cell expression of CXCR3121314151617182021. Although co-localization of monocytes/macrophages and tumor cells is necessary for engraftment, no study has systematically evaluated the role of CXCR3-expressing myeloid cells in tumor engraftment.…”

Section: Resultsmentioning

confidence: 99%

“…Reduced tumor burden in lungs was demonstrated in CXCR3 −/− mice using a long-term orthotopic (4T1 breast cancer) model12. However, it remains uncertain whether loss of host CXCR3 impaired initial engraftment or long-term survival of disseminated tumor cells.…”

Section: Resultsmentioning

confidence: 99%

“…We and others have shown that CXCR3 mediates the migration of lymphocytes and monocytes into inflamed10 and tumor-bearing11 lung. Of note, tumor-expressed CXCR3 is a key facilitator of tumor progression and metastasis in breast cancer12, colon cancer13, colorectal cancer14, osteosarcoma15, and melanoma1617. In metastatic breast cancer models, systemic pharmacologic inhibition of CXCR3 decreased lung metastasis1218, although the relative role of tumor- or myeloid-cell expressed CXCR3 could not be experimentally distinguished with this methodology.…”

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confidence: 99%

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CXCR3+ monocytes/macrophages are required for establishment of pulmonary metastases

Butler

Clancy‐Thompson

Mullins

2017

Sci Rep

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We present a new foundational role for CXCR3+ monocytes/macrophages in the process of tumor engraftment in the lung. CXCR3 is associated with monocytic and lymphocytic infiltration of inflamed or tumor-bearing lung. Although the requirement for tumor-expressed CXCR3 in metastatic engraftment has been demonstrated, the role of monocyte-expressed CXCR3 had not been appreciated. In a murine model of metastatic-like melanoma, engraftment was coordinate with CXCR3+ monocyte/macrophage accumulation in the lungs and was sensitive to pharmacologic inhibition of CXCR3 signaling. Tumor engraftment to lung was impaired in CXCR3−/− mice, and transient reconstitution with circulating CXCR3-replete monocytes was sufficient to restore engraftment. These data illustrate the paradoxical pro-tumor role for CXCR3 in lung immunobiology wherein the CXCR3 axis drives both the anti-tumor effector cell chemoattraction and pro-tumor infiltration of the lungs and suggests a potential therapeutic target for lung-tropic metastasizing cancers.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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CXCR3+ monocytes/macrophages are required for establishment of pulmonary metastases

Butler

Clancy‐Thompson

Mullins

2017

Sci Rep

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“…Animal models has been considered the standard method to study metastasis [6–8]. Generally, there are two ways to model organ specific metastasis of human cancers using laboratory mice.…”

Section: Introductionmentioning

confidence: 99%

A novel microfluidic model can mimic organ-specific metastasis of circulating tumor cells

et al. 2016

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A biomimetic microsystem might compensate costly and time-consuming animal metastatic models. Herein we developed a biomimetic microfluidic model to study cancer metastasis. Primary cells isolated from different organs were cultured on the microlfuidic model to represent individual organs. Breast and salivary gland cancer cells were driven to flow over primary cell culture chambers, mimicking dynamic adhesion of circulating tumor cells (CTCs) to endothelium in vivo. These flowing artificial CTCs showed different metastatic potentials to lung on the microfluidic model. The traditional nude mouse model of lung metastasis was performed to investigate the physiological similarity of the microfluidic model to animal models. It was found that the metastatic potential of different cancer cells assessed by the microfluidic model was in agreement with that assessed by the nude mouse model. Furthermore, it was demonstrated that the metastatic inhibitor AMD3100 inhibited lung metastasis effectively in both the microfluidic model and the nude mouse model. Then the microfluidic model was used to mimick liver and bone metastasis of CTCs and confirm the potential for research of multiple-organ metastasis. Thus, the metastasis of CTCs to different organs was reconstituted on the microfluidic model. It may expand the capabilities of traditional cell culture models, providing a low-cost, time-saving, and rapid alternative to animal models.

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“…CXCR3 expression was shown to be adversely correlated to metastasis and survival in 1800 patients. Further, knockdown or inhibition of CXCR3 was associated with reduced metastasis and improved host tumor response in a model of metastatic disease in mice (136). CXCL10 expression was found to be increased in breast cancer compared to healthy control, this increase was subsequently increased with higher grade (137).…”

Section: Discussionmentioning

confidence: 89%

The role of the androgen receptor and hydroxysteroid 17β dehydrogenase in breast cancer : Impact on tamoxifen treatment

Hilborn¹

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The healthy breast is a tissue composed of centrally located milk producing glands connected to the nipple by ducts, surrounded by fat tissue and connective tissue. The growth of the breast is primarily mediated by the estrogens, while the androgens mediate tissue homeostasis and protect against growth signals. In breast cancer, the cells of the glands or ducts undergo malignant transformation, and start proliferating in an uncontrollable fashion. Breast cancer is the most common malignancy in women, and it is estimated that 10% of all women will be diagnosed with breast cancer during their life-time. The primary classification of breast cancer is based mainly on the expression of the estrogen receptor, and 70-80% of breast cancers are estrogen receptor positive, and are classified as luminal. The remaining breast cancers are classified into HER2 positive or triple negative breast cancer. Out of all breast cancers, ~80% are androgen receptor positive. This varies in different subtypes, however, with the highest expression in luminal and lowest expression in triple negative breast cancers. The role of androgen receptor varies depending on subtype. It is considered tissue-protective in luminal breast cancer, while it's role in HER2 positive and triple negative breast cancers is less defined, but is generally considered to be associated with worse outcome. The primary treatment for breast cancer is surgery, followed by chemotherapy and/or radiotherapy in order to reduce the risk of recurrence. Treatment is also subtype specific, and luminal breast cancers in premenopausalwomen are treated using the estrogen receptor blocker (antagonist) tamoxifen, which blocks estrogen signaling. In postmenopausal women, luminal breast cancers are treated using tamoxifen or aromatase inhibitors, which prevent the formation of estrogen. The knowledge of which patient will respond and who will develop treatment resistance is of great importance, and the development of markers which can be analyzed prior to treatment in order to reduce the risk of unwanted side effects or complications is the focus of a large body of research. One of the primary goals of this thesis was to establish biomarkers for prognosis and tamoxifen treatment in breast cancer, and paper I, paper II and paper III address this aim.Steroid hormones, including estrogens and androgens, are normally synthesized from cholesterol in the adrenal gland, as well as in gender specific tissues such as ovaries in women or the testis or prostate in men. This synthesis takes place as a number of enzymatic conversions, mediated by several different enzymes, and the expression of these enzymes determines the final product of this conversion. In the adrenal gland, testis and prostate, androgens are the end-product, while the ovaries synthesize estrogens. These hormones are transported through the circulation, and upon reaching their target tissues, they mediate their effect. The impact of the steroids on their destination tissue is dependent on their relative concentration ...

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CXCR3 as a molecular target in breast cancer metastasis: inhibition of tumor cell migration and promotion of host anti-tumor immunity

Cited by 67 publications

References 42 publications

CXCR3+ monocytes/macrophages are required for establishment of pulmonary metastases

CXCR3+ monocytes/macrophages are required for establishment of pulmonary metastases

A novel microfluidic model can mimic organ-specific metastasis of circulating tumor cells

The role of the androgen receptor and hydroxysteroid 17β dehydrogenase in breast cancer : Impact on tamoxifen treatment

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