Immune Milieu Established by Postpartum Liver Involution Promotes Breast Cancer Liver Metastasis

In rodents, we identified a physiologic process within the normal liver that creates a pre-metastatic niche. This physiology is weaning-induced liver involution, characterized by hepatocyte cell death, immune influx, and extracellular matrix remodeling. Here, using weaning-induced liver involution as a model of a physiologically regulated pro-metastatic niche, we investigate how liver involution supports breast cancer metastasis. Liver metastases were induced in BALB/c immune competent hosts by portal vein injection of D2OR (low metastatic) or D2A1 (high metastatic) mouse mammary tumor cells. Tumor incidence and multiplicity increased in involution hosts with no evidence of a proliferation advantage. D2OR tumor cell extravasation, seeding, and early survival were not enhanced in the involuting group compared to the nulliparous group. Rather, the involution metastatic advantage was observed at 14 days post tumor cell injection. This metastatic advantage associated with induction of immune tolerance in the involution host liver, reproductive state dependent intra-tumoral immune composition, and CD8-dependent suppression of metastases in nulliparous hosts. Our findings suggest that the normal postpartum liver is in an immune suppressed state, which can provide a pro-metastatic advantage to circulating breast cancer cells. Potential relevance to women is suggested as a postpartum diagnosis of breast cancer is an independent predictor of liver metastasis.

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Hepatectomy, RFA, and Other Liver Directed Therapies for Treatment of Breast Cancer Liver Metastasis: A Systematic Review

Frontiers in Oncology ◽

10.3389/fonc.2021.643383 ◽

2021 ◽

Vol 11 ◽

Author(s):

Kevin Rivera ◽

Dhiresh Rohan Jeyarajah ◽

Kimberly Washington

Keyword(s):

Breast Cancer ◽

Systematic Review ◽

Liver Metastasis ◽

Hepatic Resection ◽

Cancer Metastasis ◽

Cochrane Review ◽

Hepatic Arterial Infusion ◽

Breast Cancer Metastasis ◽

Arterial Infusion ◽

Breast Cancer Liver Metastasis

BackgroundThe liver is the second most common site of breast cancer metastasis. Liver directed therapies including hepatic resection, radiofrequency ablation (RFA), transarterial chemo- and radioembolization (TACE/TARE), and hepatic arterial infusion (HAI) have been scarcely researched for breast cancer liver metastasis (BCLM). The purpose of this review is to present the known body of literature on these therapies for BCLM.MethodsA systematic review was performed with pre-specified search terms using PubMed, MEDLINE, EMBASE, and Cochrane Review resulting in 9,957 results. After review of abstracts and application of exclusion criteria, 51 studies were included in this review.ResultsHepatic resection afforded the longest median overall survival (mOS) and 5-year survival (45 mo, 41%) across 23 studies. RFA was presented in six studies with pooled mOS and 5-year survival of 38 mo and 11–33%. Disease burden and tumor size was lower amongst hepatic resection and RFA patients. TACE was presented in eight studies with pooled mOS and 1-year survival of 19.6 mo and 32–88.8%. TARE was presented in 10 studies with pooled mOS and 1-year survival of 11.5 mo and 34.5–86%. TACE and TARE populations were selected for chemo-resistant, unresectable disease. Hepatic arterial infusion was presented in five studies with pooled mOS of 11.3 months.ConclusionAlthough further studies are necessary to delineate appropriate usage of liver directed therapies in BCLM, small studies suggest hepatic resection and RFA, in well selected patients, can result in prolonged survival. Longitudinal studies with larger cohorts are warranted to further investigate the effectiveness of each modality.

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Tracking Extracellular Matrix Remodeling in Lungs Induced by Breast Cancer Metastasis. Fourier Transform Infrared Spectroscopic Studies

Molecules ◽

10.3390/molecules25010236 ◽

2020 ◽

Vol 25 (1) ◽

pp. 236 ◽

Cited By ~ 3

Author(s):

Karolina Chrabaszcz ◽

Katarzyna Kaminska ◽

Karolina Augustyniak ◽

Monika Kujdowicz ◽

Marta Smeda ◽

...

Keyword(s):

Breast Cancer ◽

Extracellular Matrix ◽

Fourier Transform ◽

Cancer Metastasis ◽

Fourier Transform Infrared ◽

Muscle Cells ◽

Breast Cancer Metastasis ◽

Extracellular Matrix Remodeling ◽

Matrix Remodeling ◽

Large Area

This work focused on a detailed assessment of lung tissue affected by metastasis of breast cancer. We used large-area chemical scanning implemented in Fourier transform infrared (FTIR) spectroscopic imaging supported with classical histological and morphological characterization. For the first time, we differentiated and defined biochemical changes due to metastasis observed in the lung parenchyma, atelectasis, fibrous, and muscle cells, as well as bronchi ciliate cells, in a qualitative and semi-quantitative manner based on spectral features. The results suggested that systematic extracellular matrix remodeling with the progress of the metastasis process evoked a decrease in the fraction of the total protein in atelectasis, fibrous, and muscle cells, as well as an increase of fibrillar proteins in the parenchyma. We also detected alterations in the secondary conformations of proteins in parenchyma and atelectasis and changes in the level of hydroxyproline residues and carbohydrate moieties in the parenchyma. The results indicate the usability of FTIR spectroscopy as a tool for the detection of extracellular matrix remodeling, thereby enabling the prediction of pre-metastatic niche formation.

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Abstract IA3: Normalizing tumor cell metabolism in breast cancer metastasis: A novel therapeutic approach

10.1158/1538-7445.tim2013-ia3 ◽

2013 ◽

Cited By ~ 1

Author(s):

Antonio F. Santidrian ◽

Akemi Matsuno-Yagi ◽

Melissa Ritland ◽

Byoung B. Seo ◽

Sarah E. LeBoeuf ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Cell ◽

Therapeutic Approach ◽

Cancer Metastasis ◽

Cell Metabolism ◽

Breast Cancer Metastasis ◽

Tumor Cell Metabolism ◽

Novel Therapeutic

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Involvement of Insulin Receptor Substrate 2 in Mammary Tumor Metastasis

Molecular and Cellular Biology ◽

10.1128/mcb.24.22.9726-9735.2004 ◽

2004 ◽

Vol 24 (22) ◽

pp. 9726-9735 ◽

Cited By ~ 79

Author(s):

Julie A. Nagle ◽

Zhefu Ma ◽

Maura A. Byrne ◽

Morris F. White ◽

Leslie M. Shaw

Keyword(s):

Breast Cancer ◽

Insulin Receptor ◽

Tumor Cells ◽

Mammary Tumor ◽

Cancer Metastasis ◽

Breast Cancer Metastasis ◽

T Antigen ◽

Insulin Receptor Substrate ◽

Mammary Tumor Cells

ABSTRACT The insulin receptor substrate (IRS) proteins are adaptor molecules that integrate signals generated by receptors that are implicated in human breast cancer. We investigated the specific contribution of IRS-2 to mammary tumor progression using transgenic mice that express the polyoma virus middle T antigen (PyV-MT) in the mammary gland and IRS-2-null (IRS-2−/−) mice. PyV-MT-induced tumor initiation and growth were similar in wild-type (WT) and IRS-2−/− mice. However, the latency and incidence of metastasis were significantly decreased in the absence of IRS-2 expression. The contribution of IRS-2 to metastasis is intrinsic to the tumor cells, because IRS-2−/− mammary tumor cells did not metastasize when grown orthotopically in the mammary fat pads of WT mice. WT and IRS-2−/− tumors contained similar numbers of mitotic cells, but IRS-2−/− tumors had a higher incidence of apoptosis than did WT tumors. In vitro, IRS-2−/− mammary tumor cells were less invasive and more apoptotic in response to growth factor deprivation than their WT counterparts. In contrast, IRS-1−/− tumor cells, which express only IRS-2, were highly invasive and were resistant to apoptotic stimuli. Collectively, our findings reveal an important contribution of IRS-2 to breast cancer metastasis.

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