Hydraulic conductivity of human cancer tissue: A hybrid study.

Background: Elevated tumor tissue interstitial fluid pressure (IFP) is an adverse biomechanical biomarker that predicts poor therapy response and an aggressive phenotype. Advances in functional imaging have opened the prospect of measuring IFP non-invasively. Image-based estimation of the IFP requires knowledge of the tissue hydraulic conductivity (K), a measure for the ease of bulk flow through the interstitium. However, data on the magnitude of K in human cancer tissue are not available. Methods: We measured the hydraulic conductivity of tumor tissue using modified Ussing chambers in surgical resection specimens. The effect of the tumor microenvironment (TME) on K was investigated by quantifying the collagen content, cell density, and fibroblast density of the tested samples using quantitative immune histochemistry. Also, we developed a computational fluid dynamics (CFD) model to evaluate the role of K on interstitial fluid flow and drug transport in solid tumors. Results: The results show that the hydraulic conductivity of human tumor tissues is very limited, ranging from approximately 10-15 to 10-14 m2/Pa∙s. Moreover, K values varied significantly between tumor types and between different samples from the same tumor. A significant inverse correlation was found between collagen fiber density and hydraulic conductivity values. However, no correlation was detected between K and cancer cell or fibroblast densities. The computational model demonstrated the impact of K on the interstitial fluid flow and the drug concentration profile: higher K values led to a lower IFP and deeper drug penetration. Conclusions: Human tumor tissue is characterized by a very limited hydraulic conductivity, representing a barrier to effective drug transport. The results of this study can inform the development of realistic computational models, facilitate non-invasive IFP estimation, and contribute to stromal targeting anticancer therapies.

Effects of Hyperthermia and Hyperthermic Intraperitoneal Chemoperfusion on the Peritoneal and Tumor Immune Contexture.

Hyperthermia combined with intraperitoneal (IP) drug delivery is increasingly used in the treatment of peritoneal metastases (PM). Hyperthermia enhances tumor perfusion and increases drug penetration after IP delivery. The peritoneum is increasingly recognized as an immune-privileged organ with its own distinct immune microenvironment. Here, we review the immune landscape of the healthy peritoneal cavity and immune contexture of peritoneal metastases. Next, we review the potential benefits and unwanted tumor-promoting effects of hyperthermia and the associated heat shock response on the tumor immune microenvironment. We highlight the potential modulating effect of hyperthermia on the biomechanical properties of tumor tissue and the consequences for immune cell infiltration. Data from translational and clinical studies are reviewed. We conclude that (mild) hyperthermia and HIPEC have the potential to enhance antitumor immunity, but detailed further studies are required to distinguish beneficial from tumor-promoting effects.

Drug transport modeling in solid tumors: A computational exploration of spatial heterogeneity of biophysical properties.

Inadequate uptake of therapeutic agents by tumor cells is still a major barrier in clinical cancer therapy. Mathematical modeling is a powerful tool to describe and investigate the transport phenomena involved. However, current models for interstitial flow and drug delivery in solid tumors have not yet embedded the existing heterogeneity of tumor biomechanical properties. The purpose of this study is to introduce a novel and more realistic methodology for computational models of solid tumor perfusion and drug delivery accounting for these regional heterogeneities as well as lymphatic drainage effects. Several tumor geometries were studied using an advanced computational fluid dynamics (CFD) modeling approach of intratumor interstitial fluid flow and drug transport. Hereby, the following novelties were implemented: (i) the heterogeneity of tumor-specific hydraulic conductivity and capillary permeability; (ii) the effect of lymphatic drainage on interstitial fluid flow and drug penetration. Tumor size and shape both have a crucial role on the interstitial fluid flow regime as well as drug transport illustrating a direct correlation with interstitial fluid pressure (IFP) and an inverse correlation with drug penetration, except for large tumors having a diameter larger than 50 mm. The results also suggest that the interstitial fluid flow and drug penetration in small tumors depend on tumor shape. A parameter study on the necrotic core size illustrated that the core effect (i.e. fluid flow and drug penetration alteration) was only profound in small tumors. Interestingly, the impact of a necrotic core on drug penetration differs depending on the tumor shape from having no effect in ideally spherical tumors to a clear effect in elliptical tumors with a necrotic core. A realistic presence of lymphatic vessels only slightly affected tumor perfusion, having no substantial effect on drug delivery. In conclusion, our findings illustrated that our novel parametric CFD modeling strategy in combination with accurate profiling of heterogeneous tumor biophysical properties can provide a powerful tool for better insights into tumor perfusion and drug transport, enabling effective therapy planning.

Interstitial fluid pressure as an emerging biomarker in solid tumors.

The physical microenvironment of cancer is characterized by elevated stiffness and tissue pressure, the main component of which is the interstitial fluid pressure (IFP). Elevated IFP is an established negative predictive and prognostic parameter, directly affecting malignant behavior and therapy response. As such, measurement of the IFP would allow to develop strategies aimed at engineering the physical microenvironment of cancer. Traditionally, IFP measurement required the use of invasive methods. Recent progress in dynamic and functional imaging methods such as dynamic contrast enhanced (DCE) magnetic resonance imaging and elastography, combined with numerical models and simulation, allows to comprehensively assess the biomechanical landscape of cancer, and may help to overcome physical barriers to drug delivery and immune cell infiltration. Here, we provide a comprehensive overview of the origin of elevated IFP, and its role in the malignant phenotype. Also, we review the methods used to measure IFP using invasive and imaging based methods, and highlight remaining obstacles and potential areas of progress in order to implement IFP measurement in clinical practice.

The pivotal role of angiogenesis in a multi-scale modeling of tumor growth exhibiting the avascular and vascular phases.

The mechanisms involved in tumor growth mainly occur at the microenvironment, where the interactions between the intracellular, intercellular and extracellular scales mediate the dynamics of tumor. In this work, we present a multi-scale model of solid tumor dynamics to simulate the avascular and vascular growth as well as tumor-induced angiogenesis. The extracellular and intercellular scales are modeled using partial differential equations and cellular Potts model, respectively. Also, few biochemical and biophysical rules control the dynamics of intracellular level. On the other hand, the growth of melanoma tumors is modeled in an animal in-vivo study to evaluate the simulation. The simulation shows that the model successfully reproduces a completed image of processes involved in tumor growth such as avascular and vascular growth as well as angiogenesis. The model incorporates the phenotypes of cancerous cells including proliferating, quiescent and necrotic cells, as well as endothelial cells during angiogenesis. The results clearly demonstrate the pivotal effect of angiogenesis on the progression of cancerous cells. Also, the model exhibits important events in tumor-induced angiogenesis like anastomosis. Moreover, the computational trend of tumor growth closely follows the observations in the experimental study.