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1. Functional assessment of migration and adhesion to quantify cancer cell aggression

   https://doi.org/10.1039/D4SM01351D  

   Mehanna, Lauren E; Boyd, James D; Walker, Chloe G; Osborne, Adrianna R; Grady, Martha E; Berron, Brad J (April 2025, Soft Matter)

   During epithelial-to-mesenchymal transition (EMT), cancer cells lose their cell–cell adhesion junctions as they become more metastatic, altering cell motility and focal adhesion disassembly associated with increased detachment from the primary tumor and a migratory response into nearby tissue and vasculature. Current in vitro strategies characterizing a cell's metastatic potential heavily favor quantifying the presence of cell adhesion biomarkers through biochemical analysis; however, mechanical cues such as adhesion and motility directly relate to cell metastatic potential without needing to first identify a cell specific biomarker for a particular type of cancer. This paper presents a comprehensive comparison of two functional metrics of cancer aggression, wound closure migration velocity and cell detachment from a culture surface, for three pairs of epithelial cancer cell lines (breast, endometrium, tongue tissue origins). It was found that one functional metric alone was not sufficient to categorize the cancer cell lines; instead, both metrics were necessary to identify functional trends and accurately place cells on the spectrum of metastasis. On average, cell lines with low metastatic potential (MCF-7, Ishikawa, and Cal-27) were more aggressive through wound closure migration compared to loss of cell adhesion. On the other hand, cell lines with high metastatic potential (MDA-MB-231, KLE, and SCC-25) were on average more aggressive through loss of cell adhesion compared to wound closure migration. This trend was true independent of the tissue type where the cells originated, indicating that there is a relationship between metastatic potential and the predominate type of cancer aggression. Our work presents one of the first combined studies relating cell metastatic potential to functional migration and adhesion metrics across cancer cell lines from selected tissue origins, without needing to identify tissue-specific biomarkers to achieve success. Using functional metrics provides powerful clinical relevancy for future predictive tools of cancer metastasis. 

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2. The Role of Fluid Shear and Metastatic Potential in Breast Cancer Cell Migration

   https://doi.org/10.1115/1.4047076  

   Riehl, Brandon D.; Kim, Eunju; Lee, Jeong Soon; Duan, Bin; Yang, Ruiguo; Donahue, Henry J.; Lim, Jung Yul (October 2020, Journal of Biomechanical Engineering)

   Abstract During the migration of cancer cells for metastasis, cancer cells can be exposed to fluid shear conditions. We examined two breast cancer cell lines, MDA-MB-468 (less metastatic) and MDA-MB-231 (more metastatic), and a benign MCF-10A epithelial cell line for their responsiveness in migration to fluid shear. We tested fluid shear at 15 dyne/cm2 that can be encountered during breast cancer cells traveling through blood vessels or metastasizing to mechanically active tissues such as bone. MCF-10A exhibited the least migration with a trend of migrating in the flow direction. Intriguingly, fluid shear played a potent role as a trigger for MDA-MB-231 cell migration, inducing directional migration along the flow with significantly increased displacement length and migration speed and decreased arrest coefficient relative to unflowed MDA-MB-231. In contrast, MDA-MB-468 cells were markedly less migratory than MDA-MB-231 cells, and responded very poorly to fluid shear. As a result, MDA-MB-468 cells did not exhibit noticeable difference in migration between static and flow conditions, as was distinct in root-mean-square (RMS) displacement—an ensemble average of all participating cells. These may suggest that the difference between more metastatic MDA-MB-231 and less metastatic MDA-MB-468 breast cancer cells could be at least partly involved with their differential responsiveness to fluid shear stimulatory cues. Our study provides new data in regard to potential crosstalk between fluid shear and metastatic potential in mediating breast cancer cell migration. 

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3. Interstitial fluid flow contributes to prostate cancer invasion and migration to bone; study conducted using a novel horizontal flow bioreactor

   https://doi.org/10.1088/1758-5090/acc09a  

   Jasuja, Haneesh; Jaswandkar, Sharad V.; Katti, Dinesh R.; Katti, Kalpana S. (March 2023, Biofabrication)

   Abstract Prostate cancer bone metastasis is the leading cause of cancer-related mortality in men in the United States, causing severe damage to skeletal tissue. The treatment of advanced-stage prostate cancer is always challenging due to limited drug treatment options, resulting in low survival rates. There is a scarcity of knowledge regarding the mechanisms associated with the effects of biomechanical cues by the interstitial fluid flow on prostate cancer cell growth and migration. We have designed a novel bioreactor system to demonstrate the impact of interstitial fluid flow on the migration of prostate cancer cells to the bone during extravasation. First, we demonstrated that a high flow rate induces apoptosis in PC3 cells via TGF-β1 mediated signaling; thus, physiological flow rate conditions are optimum for cell growth. Next, to understand the role of interstitial fluid flow in prostate cancer migration, we evaluated the migration rate of cells under static and dynamic conditions in the presence or absence of bone. We report that CXCR4 levels were not significantly changed under static and dynamic conditions, indicating that CXCR4 activation in PC3 cells is not influenced by flow conditions but by the bone, where CXCR4 levels were upregulated. The bone-upregulated CXCR4 levels led to increased MMP-9 levels resulting in a high migration rate in the presence of bone. In addition, upregulated levels ofα_vβ₃integrins under fluid flow conditions contributed to an overall increase in the migration rate of PC3 cells. Overall, this study demonstrates the potential role of interstitial fluid flow in prostate cancer invasion. Understanding the critical role of interstitial fluid flow in promoting prostate cancer cell progression will enhance current therapies for advanced-stage prostate cancer and provide improved treatment options for patients. 

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4. Metabolomics revealed the influence of breast cancer on lymphatic endothelial cell metabolism, metabolic crosstalk, and lymphangiogenic signaling in co-culture

   https://doi.org/10.1038/s41598-020-76394-7  

   Acevedo-Acevedo, Suehelay; Millar, Douglas C.; Simmons, Aaron D.; Favreau, Peter; Cobra, Paulo F.; Skala, Melissa; Palecek, Sean P. (December 2020, Scientific Reports)

   Abstract Breast cancer metastasis occurs via blood and lymphatic vessels. Breast cancer cells ‘educate’ lymphatic endothelial cells (LECs) to support tumor vascularization and growth. However, despite known metabolic alterations in breast cancer, it remains unclear how lymphatic endothelial cell metabolism is altered in the tumor microenvironment and its effect in lymphangiogenic signaling in LECs. We analyzed metabolites inside LECs in co-culture with MCF-7, MDA-MB-231, and SK-BR-3 breast cancer cell lines using $$^1\hbox {H}$$ 1 H nuclear magnetic resonance (NMR) metabolomics, Seahorse, and the spatial distribution of metabolic co-enzymes using optical redox ratio imaging to describe breast cancer-LEC metabolic crosstalk. LECs co-cultured with breast cancer cells exhibited cell-line dependent altered metabolic profiles, including significant changes in lactate concentration in breast cancer co-culture. Cell metabolic phenotype analysis using Seahorse showed LECs in co-culture exhibited reduced mitochondrial respiration, increased reliance on glycolysis and reduced metabolic flexibility. Optical redox ratio measurements revealed reduced NAD(P)H levels in LECs potentially due to increased NAD(P)H utilization to maintain redox homeostasis. $$^{13}\hbox {C}$$ 13 C -labeled glucose experiments did not reveal lactate shuttling into LECs from breast cancer cells, yet showed other $$^{13}\hbox {C}$$ 13 C signals in LECs suggesting internalized metabolites and metabolic exchange between the two cell types. We also determined that breast cancer co-culture stimulated lymphangiogenic signaling in LECs, yet activation was not stimulated by lactate alone. Increased lymphangiogenic signaling suggests paracrine signaling between LECs and breast cancer cells which could have a pro-metastatic role. 

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5. Dose-Dependent Growth Delay of Breast Cancer Xenografts in the Bone Marrow of Mice Treated with Ra-223: The Role of Bystander Effects and Their Potential for Therapy

   https://doi.org/DOI: 10.2967  

   Leung, C. N.; Canter, B. S.; Rajon, D.; Back, T. A.; Fritton, J. C.; Azzam, E. I.; Howell, R. W. (January 2020, NM Journal of nuclear medicine)

   The role of radiation-induced bystander effects in radiation therapy remains unclear. With renewed interest in therapy with alpha-particle emitters, and their potential for sterilizing disseminated tumor cells (DTCs), it is critical to determine the contribution of bystander effects to the overall response so they can be leveraged for maximum clinical benefit. Methods: Female Foxn1(nu) athymic nude mice were administered 0, 50, or 600 kBq/kg (RaCl2)-Ra-223 to create bystander conditions. At 24 hours after administration, MDA-MB-231 or MCF-7 human breast cancer cells expressing luciferase were injected into the tibial marrow compartment. Tumor burden was tracked weekly via bioluminescence. Results: The MDA-MB-231 xenografts were observed to have a 10-day growth delay in the 600 kBq/kg treatment group only. In contrast, MCF-7 cells had 7-and 65-day growth delays in the 50 and 600 kBq/kg groups, respectively. Histologic imaging of the tibial marrow compartment, alpha-camera imaging, and Monte Carlo dosimetry modeling revealed DTCs both within and beyond the range of the alpha-particles emitted from Ra-223 in bone for both MCF-7 and MDA-MB-231 cells. Conclusion: Taken together, these results support the participation of Ra-22(3)-induced antiproliferative/cytotoxic bystander effects in delayed growth of DTC xenografts. They indicate that the delay depends on the injected activity and therefore is dose-dependent. They suggest using (RaCl2)-Ra-223 as an adjuvant treatment for select patients at early stages of breast cancer. 

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