scholarly journals Platinum chemotherapy induces lymphangiogenesis to prime tissues for tumor metastasis

2019 ◽  
Author(s):  
Alexandra R. Harris ◽  
Mohammad S. Azimi ◽  
Robert Cornelison ◽  
Francesca N. Azar ◽  
Danielle C. Llaneza ◽  
...  

AbstractChemotherapy has been used to inhibit cancer growth for decades, but emerging evidence shows it can affect the tumor stroma unintentionally promoting cancer malignancy. After treatment of primary tumors, remaining drug drains via lymphatics. Though all drugs interact with the lymphatics, we know little of their impact on them. Here, we show a previously unknown effect of platinums, a widely used chemotherapeutic, to directly induce systemic VEGFR3-dependent lymphangiogenesis. These changes are dose-dependent, long-lasting, and occur in healthy and cancerous tissue in multiple mouse models of breast cancer. We saw similar effects in human ovarian and breast cancer patients whose treatment regimens included platinums. Carboplatin treatment results in lymphatic hyperplasia and secretion of pro-chemotactic factors in lymph nodes. Carboplatin treatment of healthy mice prior to mammary tumor inoculation increases cancer metastasis. These findings have broad-reaching implications for cancer patients receiving platinums and support the inclusion of anti-VEGFR3 therapy into treatment regimens.SummaryPlatinum chemotherapy induces lymphangiogenesis priming tissues for metastasis of breast cancer. Inhibition of VEGFR3 via antibody blockade can reverse these effects.


Science ◽  
2020 ◽  
Vol 367 (6485) ◽  
pp. 1468-1473 ◽  
Author(s):  
Richard Y. Ebright ◽  
Sooncheol Lee ◽  
Ben S. Wittner ◽  
Kira L. Niederhoffer ◽  
Benjamin T. Nicholson ◽  
...  

Circulating tumor cells (CTCs) are shed into the bloodstream from primary tumors, but only a small subset of these cells generates metastases. We conducted an in vivo genome-wide CRISPR activation screen in CTCs from breast cancer patients to identify genes that promote distant metastasis in mice. Genes coding for ribosomal proteins and regulators of translation were enriched in this screen. Overexpression of RPL15, which encodes a component of the large ribosomal subunit, increased metastatic growth in multiple organs and selectively enhanced translation of other ribosomal proteins and cell cycle regulators. RNA sequencing of freshly isolated CTCs from breast cancer patients revealed a subset with strong ribosome and protein synthesis signatures; these CTCs expressed proliferation and epithelial markers and correlated with poor clinical outcome. Therapies targeting this aggressive subset of CTCs may merit exploration as potential suppressors of metastatic progression.



2012 ◽  
Vol 2012 ◽  
pp. 1-5 ◽  
Author(s):  
Elena Bevilacqua ◽  
Casey A. Frankenberger ◽  
Marsha Rich Rosner

In the past decade cancer research has recognized the importance of tumorstroma interactions for the progression of primary tumors to an aggressive and invasive phenotype and for colonization of new organs in the context of metastasis. The dialogue between tumor cells and the surrounding stroma is a complex and dynamic phenomenon, as many cell types and soluble factors are involved. While the function of many of the players involved in this cross talk have been studied, the regulatory mechanisms and signaling pathways that control their expression haven’t been investigated in depth. By using a novel, interdisciplinary approach applied to the mechanism of action of the metastasis suppressor, Raf kinase inhibitory protein (RKIP), we identified a signaling pathway that suppresses invasion and metastasis through regulation of stroma-associated genes. Conceptually, the approach we developed uses a master regulator and expression arrays from breast cancer patients to formulate hypotheses based on clinical data. Experimental validation is followed by further bioinformatic analysis to establish the clinical significance of discoveries. Using RKIP as an example we show here that this multi-step approach can be used to identify gene regulatory mechanisms that affect tumor-stroma interactions that in turn influence metastasis to the bone or other organs.



2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Sanne Løkkegaard ◽  
Daniel Elias ◽  
Carla L. Alves ◽  
Martin V. Bennetzen ◽  
Anne-Vibeke Lænkholm ◽  
...  

AbstractResistance to endocrine therapy in estrogen receptor-positive (ER+) breast cancer is a major clinical problem with poorly understood mechanisms. There is an unmet need for prognostic and predictive biomarkers to allow appropriate therapeutic targeting. We evaluated the mechanism by which minichromosome maintenance protein 3 (MCM3) influences endocrine resistance and its predictive/prognostic potential in ER+ breast cancer. We discovered that ER+ breast cancer cells survive tamoxifen and letrozole treatments through upregulation of minichromosome maintenance proteins (MCMs), including MCM3, which are key molecules in the cell cycle and DNA replication. Lowering MCM3 expression in endocrine-resistant cells restored drug sensitivity and altered phosphorylation of cell cycle regulators, including p53(Ser315,33), CHK1(Ser317), and cdc25b(Ser323), suggesting that the interaction of MCM3 with cell cycle proteins is an important mechanism of overcoming replicative stress and anti-proliferative effects of endocrine treatments. Interestingly, the MCM3 levels did not affect the efficacy of growth inhibitory by CDK4/6 inhibitors. Evaluation of MCM3 levels in primary tumors from four independent cohorts of breast cancer patients receiving adjuvant tamoxifen mono-therapy or no adjuvant treatment, including the Stockholm tamoxifen (STO-3) trial, showed MCM3 to be an independent prognostic marker adding information beyond Ki67. In addition, MCM3 was shown to be a predictive marker of response to endocrine treatment. Our study reveals a coordinated signaling network centered around MCM3 that limits response to endocrine therapy in ER+ breast cancer and identifies MCM3 as a clinically useful prognostic and predictive biomarker that allows personalized treatment of ER+ breast cancer patients.



2021 ◽  
Author(s):  
Shahan Mamoor

We mined published microarray data (1) to understand the most significant gene expression differences in the tumors of triple negative breast cancer patients based on survival following treatment: dead or alive. We observed significant transcriptome-wide differential expression of DnaJ (Hsp40) homolog, subfamily C, member 28, encoded by DNAJC28 when comparing the primary tumors of triple negative breast cancer patients dead or alive. Importantly, DNAJC28 expression was correlated with overall survival in patients with breast cancer. DNAJC28 may be of relevance as a biomarker or as a molecule of interest in understanding the etiology or progression of triple negative breast cancer.



2021 ◽  
Author(s):  
Duo You ◽  
Danfeng Du ◽  
Xueke Zhao ◽  
Xinmin Li ◽  
Minfeng Ying ◽  
...  

Abstract Background: α-ketoglutarate (α-KG) is the substrate to hydoxylate collagen and hypoxia-inducible factor-1α (HIF-1α), which are important for cancer metastasis. Previous studies showed that upregulation of collagen prolyl 4-hydroxylase in breast cancer cells stabilizes HIF-1α via depleting α-KG in breast cancer cells. We propose that mitochondrial malate enzyme 2 (ME2) may also affect HIF-1α via modulating α-KG level in breast cancer cells. Methods: ME2 protein expression was evaluated by immunohistochemistry on 100 breast cancer patients and correlated with clinicopathological indicators. The effect of ME2 knockout on cancer metastasis was evaluated by an orthotopic breast cancer model. The effect of ME2 knockout or knockdown on the levels of α-KG and HIF-1α protein in breast cancer cell lines (4T1 and MDA-MB-231) was determined in vitro and in vivo.Results: The high expression of ME2 was observed in the human breast cancerous tissues compared to the matched precancerous tissues (P=0.000). The breast cancer patients with a high expression of ME2 had an inferior survival than the patients with low expression of ME2 (P=0.019). ME2 high expression in breast cancer tissues was also related with lymph node metastasis (P=0.016), pathological staging (P=0.033) and vascular cancer embolus (P=0.014). In a 4T1 orthotopic breast cancer model, ME2 knockout significantly inhibited lung metastasis. In the tumors formed by ME2 knockout 4T1 cells, α-KG level significantly increased, collagen hydroxylation level did not change significantly, but HIF-1α protein level significantly decreased, in comparison to control. In cell culture, ME2 knockout or knockdown cells demonstrated a significantly higher α-KG level but significantly lower HIF-1α protein level than control cells under hypoxia. Exogenous malate and α-KG exerted similar effect on HIF-1α in breast cancer cells to ME2 knockout or knockdown. Treatment with malate significantly decreased 4T1 breast cancer lung metastasis. ME2 expression was associated with HIF-1α level in human breast cancer samples (P=0.027).Conclusion: We provide evidence that upregulation of ME2 is associated with a poor prognosis of breast cancer patients and propose a mechanistic understanding of a link between ME2 and breast cancer metastasis.



2021 ◽  
Author(s):  
Shahan Mamoor

We mined published microarray data (1) to understand the most significant gene expression differences in the tumors of triple negative breast cancer patients based on survival following treatment: dead or alive. We observed significant transcriptome-wide differential expression of vacuolar protein sorting 52, encoded by VPS52 when comparing the primary tumors of triple negative breast cancer patients dead or alive. Importantly, VPS52 expression was correlated with recurrence-free survival in basal subtype breast cancer, a molecular subtype sharing significant overlap with triple negative breast cancer. VPS52 may be of relevance as a biomarker or as a molecule of interest in understanding the etiology or progression of triple negative breast cancer.



2021 ◽  
Author(s):  
Shahan Mamoor

We mined published microarray data (1) to understand the most significant gene expression differences in the tumors of triple negative breast cancer patients based on survival following treatment: dead or alive. We observed significant transcriptome-wide differential expression of mitogen-activated protein kinase kinase kinase kinase 2, encoded by MAP4K2 when comparing the primary tumors of triple negative breast cancer patients dead or alive. Importantly, MAP4K2 expression was correlated with distant metastasis-free survival in basal subtype breast cancer, a molecular subtype sharing significant overlap with triple negative breast cancer. MAP4K2 may be of relevance as a biomarker or as a molecule of interest in understanding the etiology or progression of triple negative breast cancer.



2020 ◽  
Author(s):  
Shahan Mamoor

Trastuzumab (Herceptin) is a monoclonal antibody targeting the extracellular domain of the human epidermal growth factor receptor 2 (HER2) (1) utilized for the treatment of adjuvant and metastatic breast cancer (2) in the United States and worldwide. We mined published and public microarray and gene expression data (3, 4) to discover in an unbiased manner the most striking transcriptional features of trastuzumab treatment. We identified significant differential expression of the gene encoding the Wnt pathway molecule dishevelled-3, DVL3 (5-7), in the primary tumors of breast cancer patients treated with trastuzumab. DVL3 expression in primary tumors of the breast in patients treated with trastuzumab was significantly higher than in patients not treated with trastuzumab.



2021 ◽  
Author(s):  
Shahan Mamoor

We mined published microarray data (1) to understand the most significant gene expression differences in the tumors of triple negative breast cancer patients based on survival following treatment: dead or alive. We observed significant transcriptome-wide differential expression of paired box 5, encoded by PAX5 when comparing the primary tumors of triple negative breast cancer patients dead or alive. Importantly, PAX5 expression was significantly correlated with overall survival in basal subtype breast cancer, a molecular subtype sharing significant overlap with triple negative breast cancer. PAX5 may be of relevance as a biomarker or as a molecule of interest in understanding the etiology or progression of triple negative breast cancer.



2020 ◽  
Author(s):  
Shahan Mamoor

Trastuzumab (Herceptin) is a monoclonal antibody targeting the extracellular domain of the human epidermal growth factor receptor 2 (HER2) (1) utilized for the treatment of adjuvant and metastatic breast cancer (2) in the United States and worldwide. We mined published microarray and gene expression data (3, 4) to discover in an unbiased manner the most striking transcriptional features of trastuzumab treatment. We identified the deleted in colorectal cancer locus DCC (5, 6) as among the genes most differentially expressed in the primary tumors of patients with breast cancer treated with trastuzumab. The primary tumors of breast cancer patients treated with trastuzumab expressed higher levels of DCC messenger RNA than did patients not treated with trastuzumab, and a single administration of trastuzumab was sufficient to result in differential expression of DCC in primary tumors of the breast, demonstrating that a gene encoding for a netrin receptor, cellular machinery utilized for axon guidance in the central nervous system (5-9), is transcriptionally induced in primary tumors of the breast following treatment with trastuzumab.



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