Elucidating the evolution of the pre-metastatic niche: Fresh insights into the soil and seed hypothesis of cancer metastasis with Raman spectroscopy (Conference Presentation)

2018 ◽  
Author(s):  
Santosh K. Paidi ◽  
Kristine Glunde ◽  
Ishan Barman
Keyword(s):  
Raman Spectroscopy ◽  
Cancer Metastasis ◽  
Metastatic Niche

scholarly journals CD133 Promotes Adhesion to the Ovarian Cancer Metastatic Niche

2018 ◽  
Vol 11 ◽  
pp. 117906441876788 ◽  
Author(s):  
Lynn Roy ◽  
Alexander Bobbs ◽  
Rachel Sattler ◽  
Jeffrey L Kurkewich ◽  
Paige B Dausinas ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Metastasis ◽  
Ex Vivo ◽  
Surface Protein ◽  
Ovarian Cancer Cells ◽  
Metastatic Niche ◽  
Attractive Therapeutic Target ◽  
Peritoneal Mesothelium

Cancer stem cells (CSCs) are an attractive therapeutic target due to their predicted role in both metastasis and chemoresistance. One of the most commonly agreed on markers for ovarian CSCs is the cell surface protein CD133. CD133+ ovarian CSCs have increased tumorigenicity, resistance to chemotherapy, and increased metastasis. Therefore, we were interested in defining how CD133 is regulated and whether it has a role in tumor metastasis. Previously we found that overexpression of the transcription factor, ARID3B, increased the expression of PROM1 (CD133 gene) in ovarian cancer cells in vitro and in xenograft tumors. We report that ARID3B directly regulates PROM1 expression. Importantly, in a xenograft mouse model of ovarian cancer, knockdown of PROM1 in cells expressing exogenous ARID3B resulted in increased survival time compared with cells expressing ARID3B and a control short hairpin RNA. This indicated that ARID3B regulation of PROM1 is critical for tumor growth. Moreover, we hypothesized that CD133 may affect metastatic spread. Given that the peritoneal mesothelium is a major site of ovarian cancer metastasis, we explored the role of PROM1 in mesothelial attachment. PROM1 expression increased adhesion to mesothelium in vitro and ex vivo. Collectively, our work demonstrates that ARID3B regulates PROM1 adhesion to the ovarian cancer metastatic niche.

scholarly journals Extracellular Vesicle-Mediated Purinergic Signaling Contributes to Host Microenvironment Plasticity and Metastasis in Triple Negative Breast Cancer

2020 ◽  
Author(s):  
Suzann Duan ◽  
Senny Nordmeier ◽  
Aidan E. Byrnes ◽  
Iain L. O. Buxton
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Endothelial Cell ◽  
Triple Negative Breast Cancer ◽  
Cancer Metastasis ◽  
Triple Negative ◽  
Purinergic Signaling ◽  
Endothelial Cell Migration ◽  
Metastatic Niche ◽  
Niche Formation

AbstractMetastasis accounts for over 90% of cancer-related deaths. The mechanisms guiding this process remain unclear. Secreted nucleoside diphosphate kinase A and B (NDPK) support breast cancer metastasis. Proteomic evidence confirms their presence in breast cancer-derived extracellular vesicles (EVs). We investigated the role of EV-associated NDPK in modulating the host microenvironment in favor of pre-metastatic niche formation. We measured NDPK expression and activity in EVs isolated from triple-negative breast cancer (MDA-MB-231) and non-tumorigenic mammary epithelial (HME1) cells using flow cytometry, western blot, and ATP assay. We evaluated the effects of EV-associated NDPK on endothelial cell migration, vascular remodeling, and metastasis. We further assessed MDA-MB-231 EV induced-proteomic changes in support of pre-metastatic lung niche formation. NDPK-B expression and phosphotransferase activity were enriched in MDA-MB-231 EVs that promote vascular endothelial cell migration and disrupt monolayer integrity. MDA-MB-231 EV-treated mice demonstrate pulmonary vascular leakage and enhanced experimental lung metastasis, whereas treatment with an NDPK inhibitor or a P2Y1 purinoreceptor antagonist blunts these effects. We identified perturbations to the purinergic signaling pathway in experimental lungs, lending evidence to support a role for EV-associated NDPK-B in lung pre-metastatic niche formation and metastatic outgrowth.

scholarly journals Fibronectin-Expressing Mesenchymal Tumor Cells Promote Breast Cancer Metastasis

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2553 ◽  
Author(s):  
Brian H. Jun ◽  
Tianqi Guo ◽  
Sarah Libring ◽  
Monica K. Chanda ◽  
Juan Sebastian Paez ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Cell Tracking ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
Mesenchymal Tumor ◽  
Minority Population ◽  
Metastatic Niche ◽  
Epithelial Tumor ◽  
Epithelial Tumor Cells ◽  
Cell Series

Tumor metastasis is connected to epithelial-mesenchymal heterogeneity (EMH) and the extracellular matrix (ECM) within the tumor microenvironment. Mesenchymal-like fibronectin (FN) expressing tumor cells enhance metastasis within tumors that have EMH. However, the secondary tumors are primarily composed of the FN null population. Interestingly, during tumor cell dissemination, the invasive front has more mesenchymal-like characteristics, although the outgrowths of metastatic colonies consist of a more epithelial-like population of cells. We hypothesize that soluble FN provided by mesenchymal-like tumor cells plays a role in supporting the survival of the more epithelial-like tumor cells within the metastatic niche in a paracrine manner. Furthermore, due to a lower rate of proliferation, the mesenchymal-like tumor cells become a minority population within the metastatic niche. In this study, we utilized a multi-parametric cell-tracking algorithm and immunoblotting to evaluate the effect of EMH on the growth and invasion of an isogenic cell series within a 3D collagen network using a microfluidic platform. Using the MCF10A progression series, we demonstrated that co-culture with FN-expressing MCF10CA1h cells significantly enhanced the survival of the more epithelial MCF10CA1a cells, with a two-fold increase in the population after 5 days in co-culture, whereas the population of the MCF10CA1a cells began to decrease after 2.5 days when cultured alone (p < 0.001). However, co-culture did not significantly alter the rate of proliferation for the more mesenchymal MCF10CA1h cells. Epithelial tumor cells not only showed prolonged survival, but migrated significantly longer distances (350 µm compared with 150 µm, respectively, p < 0.01) and with greater velocity magnitude (4.5 µm/h compared with 2.1 µm/h, respectively, p < 0.001) under co-culture conditions and in response to exogenously administered FN. Genetic depletion of FN from the MCF10CA1h cells resulted in a loss of survival and migration capacity of the epithelial and mesenchymal populations. These data suggest that mesenchymal tumor cells may function to support the survival and outgrowth of more epithelial tumor cells within the metastatic niche and that inhibition of FN production may provide a valuable target for treating metastatic disease.

scholarly journals Signals from the Metastatic Niche Regulate Early and Advanced Ovarian Cancer Metastasis through miR-4454 Downregulation

2020 ◽  
Vol 18 (8) ◽  
pp. 1202-1217 ◽  
Author(s):  
Subramanyam Dasari ◽  
Taruni Pandhiri ◽  
Tommaso Grassi ◽  
Daniel W. Visscher ◽  
Francesco Multinu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Metastasis ◽  
Advanced Ovarian Cancer ◽  
Metastatic Niche

Bone Microenvironment Tissue Surrogates Engineered for Reporting of Metastasized Breast Cancer Osteolytic Activity

2014 ◽  
Vol 1625 ◽  
Author(s):  
Jerald E. Dumas ◽  
Akia N. Parks ◽  
Manu O. Platt
Keyword(s):  
Breast Cancer ◽  
Bone Resorption ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Osteolytic Lesion ◽  
Cathepsin K ◽  
Mineral Dissolution ◽  
Bone Microenvironment ◽  
Metastatic Niche

ABSTRACTBreast cancer metastasis to bone continues to be a major clinical problem, and patient-to-patient variability in rates of disease progression and metastasis complicate treatment even further. This may be due to differences in the cancer cells, the osteoclasts, or the pre-metastatic niche, but all of these contribute to proteolytic remodeling necessary for osteolytic lesion establishment, primarily through secretion of cathepsin K, the most powerful human collagenase. There is debate about the relative contributions of breast cancer cells and osteoclasts and synergism between the two in altering the biochemical and biomechanical properties of the colonized bone, as these are difficult to parse with animal models. To quantify the relative contributions of breast cancer cells and osteoclasts in bone resorption, we have been developing engineered bone microenvironment tissue surrogates by adapting a poly(ester urethane) urea system embedded with microbone particles. Here, we report their use with MDA-MB-231 breast cancer cells and RAW264.7 derived osteoclasts, to provide temporal, multiscale reporters of bone resorption that can be measured non-destructively: 1) collagen degradation measured by C-terminal collagen fragment release, 2) mineral dissolution by measuring calcium released with the calcium arsenazo assay, and also show their beneficial effects in upregulating cathepsin K expression compared to tissue culture polystyrene controls. These more natural derived bone surrogates may be useful tools in mimicking bone metastatic niche and determining differences between proteolytic activity of different patients’ tumor and bone resident cells in a controlled manner.

scholarly journals Control of metastatic niche formation by targeting APBA3/Mint3 in inflammatory monocytes

2017 ◽  
Vol 114 (22) ◽  
pp. E4416-E4424 ◽  
Author(s):  
Toshiro Hara ◽  
Hiroki J. Nakaoka ◽  
Tetsuro Hayashi ◽  
Kouhei Mimura ◽  
Daisuke Hoshino ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cancer Cells ◽  
Cancer Metastasis ◽  
Neutralizing Antibody ◽  
Complete Suppression ◽  
Metastatic Niche ◽  
Macrophage Function ◽  
Inflammatory Monocytes ◽  
Niche Formation ◽  
Metastatic Sites

Cancer metastasis is intricately orchestrated by both cancer and normal cells, such as endothelial cells and macrophages. Monocytes/macrophages, which are often co-opted by cancer cells and promote tumor malignancy, acquire more than half of their energy from glycolysis even during normoxic conditions. This glycolytic activity is maintained during normoxia by the functions of hypoxia inducible factor 1 (HIF-1) and its activator APBA3. The mechanism by which APBA3 inhibition partially suppresses macrophage function and affects cancer metastasis is of interest in view of avoidance of the adverse effects of complete suppression of macrophage function during therapy. Here, we report that APBA3-deficient mice show reduced metastasis, with no apparent effect on primary tumor growth. APBA3 deficiency in inflammatory monocytes, which strongly express the chemokine receptor CCR2 and are recruited toward chemokine CCL2 from metastatic sites, hampers glycolysis-dependent chemotaxis of cells toward metastatic sites and inhibits VEGFA expression, similar to the effects observed with HIF-1 deficiency. Host APBA3 induces VEGFA-mediated E-selectin expression in the endothelial cells of target organs, thereby promoting extravasation of cancer cells and micrometastasis formation. Administration of E-selectin–neutralizing antibody also abolished host APBA3-mediated metastatic formation. Thus, targeting APBA3 is useful for controlling metastatic niche formation by inflammatory monocytes.

scholarly journals Exosome-Derived ADAM17 Promotes Liver Metastasis in Colorectal Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Jinbing Sun ◽  
Zhihua Lu ◽  
Wei Fu ◽  
Kuangyi Lu ◽  
Xiuwen Gu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Cancer Cells ◽  
Cancer Metastasis ◽  
Metastatic Niche ◽  
Colorectal Cancer Cells ◽  
Niche Formation ◽  
Underlying Mechanisms

Exosomes derived from cancer cells are deemed important drivers of pre-metastatic niche formation at distant organs, but the underlying mechanisms of their effects remain largely unknow. Although the role of ADAM17 in cancer cells has been well studied, the secreted ADAM17 effects transported via exosomes are less understood. Herein, we show that the level of exosome-derived ADAM17 is elevated in the serum of patients with metastatic colorectal cancer as well as in metastatic colorectal cancer cells. Furthermore, exosomal ADAM17 was shown to promote the migratory ability of colorectal cancer cells by cleaving the E-cadherin junction. Moreover, exosomal ADAM17 overexpression as well as RNA interference results highlighted its function as a tumor metastasis-promoting factor in colorectal cancer in vitro and in vivo. Taken together, our current work suggests that exosomal ADAM17 is involved in pre-metastatic niche formation and may be utilized as a blood-based biomarker of colorectal cancer metastasis.

scholarly journals Complement C5a Receptor Facilitates Cancer Metastasis by Altering T-Cell Responses in the Metastatic Niche

2014 ◽  
Vol 74 (13) ◽  
pp. 3454-3465 ◽  
Author(s):  
Surya Kumari Vadrevu ◽  
Navin K. Chintala ◽  
Sharad K. Sharma ◽  
Priya Sharma ◽  
Clayton Cleveland ◽  
...  
Keyword(s):  
T Cell ◽  
Cancer Metastasis ◽  
T Cell Responses ◽  
Metastatic Niche ◽  
C5a Receptor ◽  
Cell Responses ◽  
Complement C5a
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