The control of acidity in tumor cells: a biophysical model

Abstract

Acidosis of the tumor microenvironment leads to cancer invasion, progression and resistance to therapies. We present a biophysical model that describes how tumor cells regulate intracellular and extracellular acidity while they grow in a microenvironment characterized by increasing acidity and hypoxia. the model takes into account the dynamic interplay between glucose and O 2 consumption with lactate and CO 2 production and connects these processes to H + and HCO − 3 fluxes inside and outside cells. We have validated the model with independent experimental data and used it to investigate how and to which extent tumor cells can survive in adverse micro-environments characterized by acidity and hypoxia. the simulations show a dominance of the H + exchanges in well-oxygenated regions, and of HCO − 3 exchanges in the inner hypoxic regions where tumor cells are known to acquire malignant phenotypes. the model also includes the activity of the enzyme carbonic Anhydrase 9 (CA9), a known marker of tumor aggressiveness, and the simulations demonstrate that CA9 acts as a nonlinear pH i equalizer at any O 2 level in cells that grow in acidic extracellular environments.

Longitudinal FRET Imaging of Glucose and Lactate Dynamics and Response to Therapy in Breast Cancer Cells

“…MDA-MB-231 cells transfected with the glucose and lactate FRET reporters were incubated in DMEM with 5 mM glucose and cytochalasin B at concentrations of 0, 1, 2, and 4 μM. Images were acquired at 0, 24, and 60 h. Finally, we perturbed lactate export via monocarboxylic transporter (MCT) inhibition [37,38] using phloretin, which is both a GLUT1 and MCT4 inhibitor [17,39]. MDA-MB-231 cells transfected with the glucose and lactate FRET reporters were incubated in DMEM with 5 mM glucose and phloretin concentrations of 0, 10, and 20 μM.…”

Targeted PD-L1 PLGA/liposomes-mediated luteolin therapy for effective liver cancer cell treatment

“…Of coure, contributions of increases in acidity in the tumor microenvironment (for poly lactic acid/LDH assay-mediated increase in lactate) may cause an elevation in metastasis, angiogenesis and more importantly, immunosuppression. 13,14 Herein, we aimed to investigate the possible mechanisms underlying the impact of luteolin on the proliferation and migration of human liver cancer cells, and we constructed PD-L1-modified stealth PLGA/ Liposomes 15,16 to load luteolin to enhance the effects of drugs on cells, thus confirming the effectiveness of the constructed targeted nano-delivery system and providing experimental basis for other related studies.…”

“…A total of 5 � 10 5 HepG2 cells in the logarithmic growth phase were harvested and seeded in a 6-well plate with cell climbing pieces. 13 After the 24 hours incubation, the prepared fluorescein isothiocyanate-labeled SP/Ls (SP/Ls-FITC) and FITC labeled PD-SP/Ls (PD-SP/Ls-FITC) were added, and the 6-well plate was placed in an incubator for further culture. At specific time points, the cells climbing pieces were taken out with camps, washed with cold PBS buffer solution for 3 times and placed in 4% paraformaldehyde for fixation.…”

Tumor-Associated Macrophages: Critical Players in Drug Resistance of Breast Cancer

“…In addition, an in silico model have been developed to study the effect of TAM on tumor cell migration (143). Through these new models, we can more accurately study the influence of various components in TIME on tumor therapy, which is also conducive to the study of targeting TAM to overcome drug resistance in BCC treatment (144)(145)(146). So, the knowledge of BC immunotherapy needs further investigation in the future.…”