scholarly journals Breast tumor stiffness instructs bone metastasis via mechanical memory

2019 ◽  
Author(s):  
Adam W Watson ◽  
Adam Grant ◽  
Sara S Parker ◽  
Michael W Harman ◽  
Mackenzie R Roman ◽  
...  
Keyword(s):  
Bone Metastasis ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Primary Tumor ◽  
Target Genes ◽  
Gene Expression Measurement ◽  
Mechanical Stimuli ◽  
Mechanical Memory ◽  
Tumor Stiffness

The mechanical microenvironment of primary breast tumors plays a substantial role in promoting tumor progression. While the transitory response of cancer cells to pathological stiffness in their native microenvironment has been well described, it is still unclear how mechanical stimuli in the primary tumor influence distant, late-stage metastatic phenotypes across time and space in absentia. Here, we show that primary tumor stiffness promotes stable, non-genetically heritable phenotypes in breast cancer cells. This mechanical memory instructs cancer cells to adopt and maintain increased cytoskeletal dynamics, traction force, and 3D invasion in vitro, in addition to promoting osteolytic bone metastasis in vivo. Furthermore, we established a mechanical conditioning (MeCo) score comprised of mechanically-regulated genes as a global gene expression measurement of tumor stiffness response. Clinically, we show that a high MeCo score is strongly associated with bone metastasis in patients. Using a discovery approach, we mechanistically traced mechanical memory in part to ERK-mediated mechanotransductive activation of RUNX2, an osteogenic gene bookmarker and bone metastasis driver. The combination of these RUNX2 traits permits the stable transactivation of osteolytic target genes that remain upregulated after cancer cells disseminate from their activating microenvironment in order to modify a distant microenvironment. Using genetic, epigenetic, and functional approaches, we were able to simulate, repress, select and extend RUNX2-mediated mechanical memory and alter cancer cell behavior accordingly. In concert with previous studies detailing the influence of biochemical properties of the primary tumor stroma on distinct metastatic phenotypes, our findings detailing the influence of biomechanical properties support a generalized model of cancer progression in which the integrated properties of the primary tumor microenvironment govern the secondary tumor microenvironment, i.e., soil instructs soil.

Calcineurin regulates the stability and activity of estrogen receptor α

2021 ◽  
Vol 118 (44) ◽  
pp. e2114258118
Author(s):  
Takahiro Masaki ◽  
Makoto Habara ◽  
Yuki Sato ◽  
Takahiro Goshima ◽  
Keisuke Maeda ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Breast Cancer Cells ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Estrogen Receptor Α ◽  
The Stability ◽  
Positive Breast Cancer

Estrogen receptor α (ER-α) mediates estrogen-dependent cancer progression and is expressed in most breast cancer cells. However, the molecular mechanisms underlying the regulation of the cellular abundance and activity of ER-α remain unclear. We here show that the protein phosphatase calcineurin regulates both ER-α stability and activity in human breast cancer cells. Calcineurin depletion or inhibition down-regulated the abundance of ER-α by promoting its polyubiquitination and degradation. Calcineurin inhibition also promoted the binding of ER-α to the E3 ubiquitin ligase E6AP, and calcineurin mediated the dephosphorylation of ER-α at Ser294 in vitro. Moreover, the ER-α (S294A) mutant was more stable and activated the expression of ER-α target genes to a greater extent compared with the wild-type protein, whereas the extents of its interaction with E6AP and polyubiquitination were attenuated. These results suggest that the phosphorylation of ER-α at Ser294 promotes its binding to E6AP and consequent degradation. Calcineurin was also found to be required for the phosphorylation of ER-α at Ser118 by mechanistic target of rapamycin complex 1 and the consequent activation of ER-α in response to β-estradiol treatment. Our study thus indicates that calcineurin controls both the stability and activity of ER-α by regulating its phosphorylation at Ser294 and Ser118. Finally, the expression of the calcineurin A–α gene (PPP3CA) was associated with poor prognosis in ER-α–positive breast cancer patients treated with tamoxifen or other endocrine therapeutic agents. Calcineurin is thus a promising target for the development of therapies for ER-α–positive breast cancer.

scholarly journals Metabolic Alterations in Pancreatic Cancer Progression

Cancers ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 2 ◽  
Author(s):  
Enza Vernucci ◽  
Jaime Abrego ◽  
Venugopal Gunda ◽  
Surendra K. Shukla ◽  
Aneesha Dasgupta ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Precancerous Lesions ◽  
Genetically Engineered ◽  
Metabolic Reprogramming ◽  
Pancreatic Tumors ◽  
Metabolic Alterations ◽  
Genetically Engineered Mice

Pancreatic cancer is the third leading cause of cancer-related deaths in the USA. Pancreatic tumors are characterized by enhanced glycolytic metabolism promoted by a hypoxic tumor microenvironment and a resultant acidic milieu. The metabolic reprogramming allows cancer cells to survive hostile microenvironments. Through the analysis of the principal metabolic pathways, we identified the specific metabolites that are altered during pancreatic cancer progression in the spontaneous progression (KPC) mouse model. Genetically engineered mice exhibited metabolic alterations during PanINs formation, even before the tumor development. To account for other cells in the tumor microenvironment and to focus on metabolic adaptations concerning tumorigenic cells only, we compared the metabolic profile of KPC and orthotopic tumors with those obtained from KPC-tumor derived cell lines. We observed significant upregulation of glycolysis and the pentose phosphate pathway metabolites even at the early stages of pathogenesis. Other biosynthetic pathways also demonstrated a few common perturbations. While some of the metabolic changes in tumor cells are not detectable in orthotopic and spontaneous tumors, a significant number of tumor cell-intrinsic metabolic alterations are readily detectable in the animal models. Overall, we identified that metabolic alterations in precancerous lesions are maintained during cancer development and are largely mirrored by cancer cells in culture conditions.

scholarly journals miR-216a Acts as a Negative Regulator of Breast Cancer by Modulating Stemness Properties and Tumor Microenvironment

2020 ◽  
Vol 21 (7) ◽  
pp. 2313 ◽  
Author(s):  
Giuseppina Roscigno ◽  
Assunta Cirella ◽  
Alessandra Affinito ◽  
Cristina Quintavalle ◽  
Iolanda Scognamiglio ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Tumor Microenvironment ◽  
Cancer Stem Cells ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Negative Regulator ◽  
Mammosphere Formation ◽  
Incidence And Mortality ◽  
Cells Of The Microenvironment

Breast cancer is the most frequent malignancy in females in terms of both incidence and mortality. Underlying the high mortality rate is the presence of cancer stem cells, which divide indefinitely and are resistant to conventional chemotherapies, so causing tumor relapse. In the present study, we identify miR-216a-5p as a downregulated microRNA in breast cancer stem cells vs. the differentiated counterpart. We demonstrate that overexpression of miR-216a-5p impairs stemness markers, mammosphere formation, ALDH activity, and the level of Toll-like receptor 4 (TLR4), which plays a significant role in breast cancer progression and metastasis by leading to the release of pro-inflammatory molecules, such as interleukin 6 (IL-6). Indeed, miR-216a regulates the crosstalk between cancer cells and the cells of the microenvironment, in particular cancer-associated fibroblasts (CAFs), through regulation of the TLR4/IL6 pathway. Thus, miR-216a has an important role in the regulation of stem phenotype, decreasing stem-like properties and affecting the cross-talk between cancer cells and the tumor microenvironment.

scholarly journals Cytokine Secretions in Partial Breast Tumor Microenvironment With and Without Sulforaphane

2021 ◽  
Vol 5 (Supplement_2) ◽  
pp. 274-274
Author(s):  
Courtney Merrick ◽  
Lauren Housley
Keyword(s):  
Breast Cancer ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Treatment Options ◽  
Graduate Studies ◽  
Gm Csf ◽  
Funding Sources ◽  
Cytokine Levels ◽  
Vital Cell

Abstract Objectives Triple-negative breast cancer (TNBC) comprises 10–20% of breast cancer cases. It is particularly aggressive with limited and deleterious treatment options. Increasingly, research confirms that communication between cancer cells and neighboring macrophages promotes disease progression in part by secretion of cytokines that increase tumor cell proliferation, invasion, and metastasis. Sulforaphane (SFN) is a chemopreventive phytochemical found in cruciferous vegetables (broccoli) shown to alter cytokine secretion in macrophages and breast cancer cells grown in single culture. However, its effect in the tumor microenvironment remains unclear. This study aims to characterize cytokine profiles in media where TNBC cells and macrophages are grown in coculture with and without SFN treatment. We expect SFN to modify cytokine secretions in coculture media, suggesting SFN may disrupt vital cell-cell signaling needed for cancer progression. Methods TNBC cells (MDA-MB-231) were grown in Transwell plates with and without macrophages (THP-1 cells differentiated with PMA). Cell cultures (n = 3) were treated with either 15 μM SFN, DMSO (vehicle-control), or a non-treatment control. Cytokine levels were evaluated in media at 24 and 48 hours after treatment using BioPlex 2000 assay. Results Treatment with sulforaphane significantly reduced the levels of several targets in coculture including IL-1ra, IL-4, IL-5, IL-10, IL-12, IL-13, IL-15, IL-17, CCL2 (MCP-1), CCL11, CCL22, CCL26, CXCL12, IFN-y, G-CSF, GM-CSF, Eotaxin, and VEGF. Conversely, MIF was elevated following treatment. Effects were discovered at 24-hour and 48-hour time points. Conclusions We demonstrated that SFN altered the levels of numerous cellular signaling proteins in cancer cell-macrophage coculture, many of which are known to be involved with breast cancer progression. These results reveal mechanistic links underlying SFNs chemopreventive function and bolster SFNs potential as a treatment strategy for TNBC. Funding Sources Department of Nutrition and Food Science, CSU Chico; Graduate Studies, CSU Chico; CSUPERB: CSU Program for Education and Research in Biotechnology.

scholarly journals Nerves in the Tumor Microenvironment: Origin and Effects

2020 ◽  
Vol 8 ◽  
Author(s):  
Wenjun Wang ◽  
Lingyu Li ◽  
Naifei Chen ◽  
Chao Niu ◽  
Zhi Li ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Perineural Invasion ◽  
Vital Role ◽  
Cancer Growth ◽  
Alternative Route ◽  
Sympathetic Nervous ◽  
Molecular Bases

Studies have reported the vital role of nerves in tumorigenesis and cancer progression. Nerves infiltrate the tumor microenvironment thereby enhancing cancer growth and metastasis. Perineural invasion, a process by which cancer cells invade the surrounding nerves, provides an alternative route for metastasis and generation of tumor-related pain. Moreover, central and sympathetic nervous system dysfunctions and psychological stress-induced hormone network disorders may influence the malignant progression of cancer through multiple mechanisms. This reciprocal interaction between nerves and cancer cells provides novel insights into the cellular and molecular bases of tumorigenesis. In addition, they point to the potential utility of anti-neurogenic therapies. This review describes the evolving cross-talk between nerves and cancer cells, thus uncovers potential therapeutic targets for cancer.

scholarly journals A mechanical memory of pancreatic cancer cells

2019 ◽  
Author(s):  
Ilaria Carnevale ◽  
Mjriam Capula ◽  
Elisa Giovannetti ◽  
Thomas Schmidt ◽  
Stefano Coppola
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Nuclear Translocation ◽  
Traction Force ◽  
Long Term Memory ◽  
Mechanical Stimuli ◽  
Mechanical Adaptation ◽  
Pancreatic Cancer Cells ◽  
Mechanical Memory

Cells sense and respond to mechanical stimuli in healthy and pathological conditions. Although the major mechanisms un-derlying cellular mechanotransduction have been described, it remains largely unclear how cells store information on past mechanical cues over time. Such mechanical memory is extremely relevant in the onset of metastasis in which cancer cells migrate through tissues of different stiffness, e.g. from a stiffer tumor microenvironment to softer metastatic sites as commonly occurs for pancreatic cancer. Here, we used micropillar-based traction force microscopy to show that Suit-2.28 pancreatic cancer cells mechanically primed on a stiff matrix exerted higher traction forces even when transferred to a soft secondary matrix, as compared to soft-primed cells. This mechanical memory effect was mediated by the Yes-associated protein (YAP) and the microRNA-21 (miR-21) that are two mechanosensors initially identified as long-term memory keepers in mesenchymal stem cells. Soft-primed cells showed (i) a lower YAP nuclear translocation when transferred to a stiff secondary matrix and (ii) a loss of rigidity sensing through YAP, as compared to stiff-primed cells. The mechanical adaptation resulted in a differential expression of miR-21, inversely proportional to the priming rigidity. The long-term mechanical memory retained by miR-21 unveiled a previously unidentified mechanical modulation of drug resistance by past matrix stiffness. The higher expression of miR-21 in soft-primed cells correlated with the increased resistance to gemcitabine, as compared to stiff-primed and non-primed pancreatic cancer cells.

scholarly journals Bridging angiogenesis and immune evasion in the hypoxic tumor microenvironment

2018 ◽  
Vol 315 (6) ◽  
pp. R1072-R1084 ◽  
Author(s):  
Luana Schito
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Tumor Vasculature ◽  
Antiangiogenic Agents ◽  
Pathophysiological Mechanism ◽  
Feedforward Loop ◽  
Antiangiogenic Therapies ◽  
Solid Malignancies ◽  
Hypoxic Tumor

Hypoxia (low O2) is a ubiquitous microenvironmental factor promoting cancer progression, metastasis, and mortality, owing to the ability of cancer cells to co-opt physiological angiogenic responses. Notwithstanding, the pathophysiological induction of angiogenesis results in an abnormal tumor vasculature, further aggravating hypoxia in a feedforward loop that limits the efficacy of molecular targeted therapies. Recent studies suggest that, besides their canonical roles, angiogenic factors promote a panoply of immunosuppressive effects in the tumor microenvironment. Therefore, intratumoral hypoxia emerges as a hitherto unrecognized mechanism evolutionarily repurposing angiogenic molecules as (patho)physiological immunomodulators. On the other hand, antiangiogenic therapies could be aimed at impeding both tumor growth and immunotolerance toward cancer cells, a beneficial effect that can be countered if hypoxia signaling pathways are left unchecked, leading to therapeutic failure. This review summarizes evidence supporting the hypothesis that hypoxia acts as a common pathophysiological mechanism of resistance to immunotherapeutic and antiangiogenic agents while proposing potential strategies to curtail resistance and mortality in patients bearing solid malignancies.

scholarly journals Emerging Autophagy Functions Shape the Tumor Microenvironment and Play a Role in Cancer Progression - Implications for Cancer Therapy

2020 ◽  
Vol 10 ◽  
Author(s):  
Silvina Odete Bustos ◽  
Fernanda Antunes ◽  
Maria Cristina Rangel ◽  
Roger Chammas
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Therapy ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Stress Responses ◽  
Epithelial Mesenchymal Transition ◽  
Metastatic Potential ◽  
Secretory Proteins ◽  
Mesenchymal Transition ◽  
Independent Functions

The tumor microenvironment (TME) is a complex environment where cancer cells reside and interact with different types of cells, secreted factors, and the extracellular matrix. Additionally, TME is shaped by several processes, such as autophagy. Autophagy has emerged as a conserved intracellular degradation pathway for clearance of damaged organelles or aberrant proteins. With its central role, autophagy maintains the cellular homeostasis and orchestrates stress responses, playing opposite roles in tumorigenesis. During tumor development, autophagy also mediates autophagy-independent functions associated with several hallmarks of cancer, and therefore exerting several effects on tumor suppression and/or tumor promotion mechanisms. Beyond the concept of degradation, new different forms of autophagy have been described as modulators of cancer progression, such as secretory autophagy enabling intercellular communication in the TME by cargo release. In this context, the synthesis of senescence-associated secretory proteins by autophagy lead to a senescent phenotype. Besides disturbing tumor treatment responses, autophagy also participates in innate and adaptive immune signaling. Furthermore, recent studies have indicated intricate crosstalk between autophagy and the epithelial-mesenchymal transition (EMT), by which cancer cells obtain an invasive phenotype and metastatic potential. Thus, autophagy in the cancer context is far broader and complex than just a cell energy sensing mechanism. In this scenario, we will discuss the key roles of autophagy in the TME and surrounding cells, contributing to cancer development and progression/EMT. Finally, the potential intervention in autophagy processes as a strategy for cancer therapy will be addressed.

MicroRNA-mutant P53 crosstalk in chemoresistance: a hint to monitor therapy outcome

MicroRNA ◽  
2020 ◽  
Vol 09 ◽  
Author(s):  
Andrea Speciale ◽  
Paola Monti ◽  
Gilberto Fronza ◽  
Alberto Izzotti ◽  
Paola Menichini
Keyword(s):  
Cell Cycle ◽  
Cell Migration ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Target Genes ◽  
Therapy Outcome ◽  
In Vivo Studies ◽  
Mutant P53 ◽  
Altered Expression ◽  
Monitoring Therapy

: The chemoresistance of cancer cells is a multifactorial mechanism, in which de-regulated apoptotic pathways, the oxidative response and cancer cell migration play a crucial role. A key player in the control of such pathways is the tumor suppressor gene TP53, also defined as the “guardian of the genome”, encoding the P53 tetrameric transcription factor. P53, following cell injuries, can activate the transcription of several target genes crucial for the induction of apoptosis, cell cycle arrest, modulation of senescence, DNA repair, autophagy and metabolism. Importantly, TP53 gene is mutated in nearly 50% of human cancers, implying an altered expression of target genes in cancer cells. The presence of TP53 mutations can also affect the expression of several small non-coding RNAs (microRNAs or miRNAs), involved in the same regulation of the apoptotic signaling, cell cycle regulation and cell migration. In mutant P53 expressing tumors, some miRNAs resulted to be down-regulated, while others appeared to be up-regulated as demonstrated by in vitro and in vivo studies. Thus, the expression level of specific P53 responsive miRNAs could be used as a marker of cancer progression and therapy performance. In the present review, we will summarize the role of P53-related miRNAs and their clinical relevance in monitoring therapy outcome and progression of cancers with mutant P53.

Platelet Depletion Reduces Tumor Hypoxia and Metastasis Mediated by Met Signaling Pathway

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3321-3321
Author(s):  
Rong Li ◽  
Meiping Ren ◽  
Ni Chen ◽  
Mao Luo ◽  
Jianbo Wu
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Primary Tumor ◽  
Tumor Hypoxia ◽  
Hemoglobin Content ◽  
Melanoma Cancer ◽  
And Control ◽  
Platelet Depletion

Abstract Abstract 3321 Platelets play a fundamental role in maintaining hemostasis and have been shown to participate in hemorrhagic metastasis. However, the role of platelets in the tumor growth, angiogenesis, and metastasis initiation remains undefined. The B16/F10 melanoma cancer cells model of metastasis and the Lewis lung carcinoma (LLC) spontaneous pulmonary metastasis model were used for this purpose. Using induction of thrombocytopenia, primary tumor growth was monitored and every 3 days anti-GPIbα or rat IgG injections were initiated when tumor reached ∼500mm3and continued until tumor reached to 3 weeks. We showed that platelet depletion had no change in tumor growth but reduced metastasis. Platelet depletion significantly increased pericyte coverage and reduced vascular density compared with control mice. We evaluated the ratio of fluorescence intensities within the plasma and tumor following injection of mice with FITC-dextran. We found that the FITC-dextran was similarly deposited into the tumor tissue in either platelet-depleted or control mice, indicating that tumor vessel perfusion did not differ in either platelet-depleted or control mice. To further gain insight into the molecular mechanisms associated with reduced metastasis resulting from platelet depletion, we assessed hypoxia levels by examining pimonidazole adduct formation in the tumors of platelet-depleted and control mice and found decreased hypoxic levels in the platelet-depleted tumors. In addition, expression of the hypoxia-inducible transcription factor HIF-1α was also significantly reduced in the tumors of platelet-depleted mice. Tumor hypoxia is strongly associated with deposition of hemoglobin. We measured the intratumor hemoglobin content, reflecting the level of erythrocytes extravasation. The hemoglobin content in the tumors of mice with platelet-depletion was significantly higher than that of control mice (172.11 ± 20.2 g/L/g Vs. 110.28 ± 12.4 g/L/g, p<0.05) Based on the known induction effects of hypoxia and cancer invasiveness on the expression and activation of the proinvasive tyrosine kinase receptor Met, we analyzed total protein and tyrosine phosphorylation levels of Met in both platelet-depleted and control mice. Western blotting analysis revealed that platelet-depletion caused a significantly decrease of both total Met and phosph-Met in tumors when compared to tumors from control mice. To evaluate intratumoral growth factor level, microdialysis was performed after 3 weeks and there was a significant decrease of extracellular VEGF and TNF-β in platelet depletion mice compared with control mice. Recent studies demonstrated that abundant platelets were detected in the tumor microenvironment apart from the vasculature. Based on the finding platelets in contact with tumor cells outside the bloodstream, we examined the functional effects of co-implantation of B16/F10 tumor cells with platelets on tumor progression and metastasis. B16/F10 melanoma cancer cells were implanted into back of wild type mice. During a 3-weeks growth, co-implantation of B16/F10 with platelets not only led to promoted tumor volume (3968 ± 296 mm3Vs. 2956 ± 180 mm3, p<0.05) and weight (5.529 ± 0.35 g Vs. 3.943 ± 0.738 g, p<0.05 ) compared with B16/F10 alone implantation, but also led to an increase in metastasis. Furthermore, in vitro co-culture of B16/F10 cancer cells with platelets showed a significant increase in B16/F10 cancer cells invasion compared with B16/F10 cancer cells alone. In conclusion, our findings demonstrate for the first time that platelets play a critical role in the initiation of tumor metastasis. Moreover, our findings suggest that platelets within the primary tumor microenvironment are likely involved in tumor progression and metastasis. Disclosures: No relevant conflicts of interest to declare.

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