Molecular Mechanisms of Breast Cancer Metastasis to the Lung: Clinical and Experimental Perspectives

Medeiros, Braeden; Allan, Alison L.

doi:10.3390/ijms20092272

Cited by 183 publications

(133 citation statements)

References 124 publications

(125 reference statements)

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“…In addition to determining how the presence of a TN primary breast tumor influences the lung ECM, we also investigated the effect on the soluble lung microenvironment. The lung produces soluble factors (cytokines, chemokines, growth factors and soluble ECM proteins) which are crucial for mediating pulmonary metastasis [40]. Previous work by our laboratory has demonstrated that the normal physiological lung in tumor naïve mice produces various soluble factors that promote metastatic behavior [9]; however, the ability of the primary tumor to further enhance the soluble lung microenvironment in preparation for metastasis has not been investigated.…”

Section: Discussionmentioning

confidence: 99%

Triple-Negative Primary Breast Tumors Induce Supportive Premetastatic Changes in the Extracellular Matrix and Soluble Components of the Lung Microenvironment

Medeiros

Goodale

Postenka

et al. 2020

Cancers

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The lung is one of the deadliest sites of breast cancer metastasis, particularly in patients with triple-negative (TN) disease. We hypothesized that the presence of a TN primary breast tumor induces changes in the extracellular matrix (ECM) and soluble components of the lung microenvironment that support metastatic behavior. SUM159 (TN) and MCF7 (luminal A) breast cancer cells were injected into mice, and primary breast tumors were established prior to assessing metastatic niche changes. We observed increased CD117+ hematopoietic progenitor cells in the bone marrow of SUM159 mice versus MCF7 or control mice (p < 0.05). Relative to mice bearing MCF7 tumors and non-tumor controls, mice bearing SUM159 tumors demonstrated enhanced expression of ECM proteins in the lung (fibronectin, tenascin-c and periostin), with similar changes observed in lung fibroblasts treated with extracellular vesicles (EVs) from TN breast cancer cells (p < 0.05). Exposure to lung-conditioned media (LCM) from SUM159 tumor-bearing mice resulted in increased migration/proliferation of both SUM159 and MCF7 cells relative to the control (p < 0.05). In contrast, LCM from MCF-7 tumor-bearing mice had no such effect. LCM from SUM159 tumor-bearing mice contained 16 unique proteins relative to other LCM conditions, including the metastasis-associated proteins CCL7, FGFR4, GM-CSF, MMP3, thrombospondin-1 and VEGF. These findings suggest for the first time that the TN breast cancer molecular subtype may be an important determinant of premetastatic changes to both the ECM and soluble components of the lung, potentially mediated via breast cancer-derived EVs.

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Section: Discussionmentioning

confidence: 99%

Triple-Negative Primary Breast Tumors Induce Supportive Premetastatic Changes in the Extracellular Matrix and Soluble Components of the Lung Microenvironment

Medeiros

Goodale

Postenka

et al. 2020

Cancers

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“…Cancer cell adhesion and the subsequent transmigration across endothelium to distant organs is a crucial step of metastasis. Organ-specific colonisation is a key feature of most metastatic cancer cells, and breast cancer cells tend to infiltrate the bone, brain, liver and lungs [ 2 , 3 , 4 , 5 ]. Despite the extensive literature, the mechanisms that promote the adhesion of breast cancer cells to organ-specific endothelial layers remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Protein Disulphide Isomerase A1 Is Involved in the Regulation of Breast Cancer Cell Adhesion and Transmigration via Lung Microvascular Endothelial Cells

Stojak

Milczarek

Kurpińska

et al. 2020

Cancers

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Cancer cell cross-talk with the host endothelium plays a crucial role in metastasis, but the underlying mechanisms are still not fully understood. We studied the involvement of protein disulphide isomerase A1 (PDIA1) in human breast cancer cell (MCF-7 and MDA-MB-231) adhesion and transendothelial migration. For comparison, the role of PDIA1 in proliferation, migration, cell cycle and apoptosis was also assessed. Pharmacological inhibitor, bepristat 2a and PDIA1 silencing were used to inhibit PDIA1. Inhibition of PDIA1 by bepristat 2a markedly decreased the adhesion of breast cancer cells to collagen type I, fibronectin and human lung microvascular endothelial cells. Transendothelial migration of breast cancer cells across the endothelial monolayer was also inhibited by bepristat 2a, an effect not associated with changes in ICAM-1 expression or changes in cellular bioenergetics. The silencing of PDIA1 produced less pronounced anti-adhesive effects. However, inhibiting extracellular free thiols by non-penetrating blocker p-chloromercuribenzene sulphonate substantially inhibited adhesion. Using a proteomic approach, we identified that β1 and α2 integrins were the most abundant among all integrins in breast cancer cells as well as in lung microvascular endothelial cells, suggesting that integrins could represent a target for PDIA1. In conclusion, extracellular PDIA1 plays a major role in regulating the adhesion of cancer cells and their transendothelial migration, in addition to regulating cell cycle and caspase 3/7 activation by intracellular PDIA1. PDIA1-dependent regulation of cancer–endothelial cell interactions involves disulphide exchange and most likely integrin activation but is not mediated by the regulation of ICAM-1 expression or changes in cellular bioenergetics in breast cancer or endothelial cells.

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“…Breast cancer cells released from the primary tumour may also spread to the lungs. 49 Lung metastasis is usually observed 5 years after initial breast cancer diagnosis, with >60% mortality rate following lung metastasis. 49 The subtype of breast cancer affects the frequency of lung metastasis.…”

Section: Metastasis To the Lungsmentioning

confidence: 99%

Metastasis: A Bane of Breast Cancer Therapy

2020

EMJ

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The underlying mechanisms of metastasis in patients with breast cancer is still poorly understood. Approximately 6% of patients with breast cancer present with metastasis at the time of diagnosis. Metastatic breast cancer is difficult to treat and patients with breast cancer with distant metastasis have a significantly lower 5-year survival rate compared to patients with localised breast cancer (27% and 99%, respectively). During breast cancer progression, tumour cells first metastasise to nearby draining lymph nodes and then to distant organs, primarily bone, lungs, liver, and brain. In this brief review, the authors discuss breast cancer metastasis, the role of epithelial–mesenchymal transition and the contributions of the immune system to the metastatic process. The authors also briefly discuss whether there is any relationship between tumour size and metastatic potential, and recent advances in treatment for metastatic breast cancer. The studies highlighted suggest that immunotherapy may play a more significant role in future patient care for metastatic breast cancer.

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Molecular Mechanisms of Breast Cancer Metastasis to the Lung: Clinical and Experimental Perspectives

Cited by 183 publications

References 124 publications

Triple-Negative Primary Breast Tumors Induce Supportive Premetastatic Changes in the Extracellular Matrix and Soluble Components of the Lung Microenvironment

Triple-Negative Primary Breast Tumors Induce Supportive Premetastatic Changes in the Extracellular Matrix and Soluble Components of the Lung Microenvironment

Protein Disulphide Isomerase A1 Is Involved in the Regulation of Breast Cancer Cell Adhesion and Transmigration via Lung Microvascular Endothelial Cells

Metastasis: A Bane of Breast Cancer Therapy

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