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Author Spotlight: A Model to Study the Systemic and Local Dynamics of CD8+ T Cells During LN Metastasis
Published on: January 26, 2024
Melanoma growth effects on molecular clearance from tumors and biodistribution into systemic tissues versus draining
Nathan Andrew Rohner1, Susan Napier Thomas2
1George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States; Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia, United States.
Abstract:
Factors produced within or administered directly into the tumor interstitium, such as cytokines, chemokines, proteases, exosomes, microvesicles, or therapeutic agents, play important and multifaceted roles in the regulation of malignant disease progression. Their bioavailability to mediate signaling in distributed tissues outside of the tumor microenvironment, however, has not been well described. We therefore sought to elucidate the relative extent to which factors from within the primary tumor disseminate to systemic tissues as well as how these distribution profiles are influenced by both hydrodynamic size and the remodeling tumor vasculature. To accomplish this goal, we intratumorally co-infused into the dermal lesions of B16F10 melanoma-bearing mice at prescribed times post tumor implantation a near infrared fluorescent tracer panel ranging from 5 to 500nm in hydrodynamic diameter and compared the in vivo clearance and biodistribution profiles to that of naïve animals. Our results indicate that tumor growth reduces tumor-draining lymph node accumulation and alters the distribution of tumor-derived factors amongst systemic tissues. Despite these changes, previously developed principles of size-dependent lymph node drug targeting are conserved in melanomas, suggesting their applicability to sentinel lymph node-targeted drug delivery. Tumor progression was also found to result in a significant increase in the hydrodynamic size of factors originating from the tumor that accumulated within systemic tissues. This suggests that tumor vascular remodeling may redirect the organism-wide signaling activity of tumor-derived factors and may negatively contribute to disease progression by altering the bioavailability of molecules important to the regulation of pre-metastatic niche formation and the induction of anti-tumor immunity.
Insights
Tumor growth alters how factors spread to the whole body, affecting signaling and potentially disease progression. Size-dependent lymph node targeting principles remain applicable for melanoma drug delivery.
Area of Science:
- Oncology
- Cancer Biology
- Pharmacology
Background:
- Tumor-derived factors regulate malignant disease progression.
- Systemic bioavailability of tumor interstitium factors is poorly understood.
- Tumor vasculature remodeling influences factor dissemination.
Purpose of the Study:
- To determine the dissemination extent of primary tumor factors to systemic tissues.
- To investigate how hydrodynamic size and tumor vasculature remodeling affect factor distribution profiles.
Main Methods:
- Intratumoral co-infusion of fluorescent tracers (5-500nm hydrodynamic diameter) into B16F10 melanoma-bearing mice.
- Comparison of in vivo clearance and biodistribution profiles with naive animals.
- Analysis of tumor growth impact on factor dissemination and systemic accumulation.
Main Results:
- Tumor growth reduces lymph node accumulation and alters systemic distribution of tumor-derived factors.
- Size-dependent lymph node drug targeting principles are conserved in melanomas.
- Tumor progression increases the hydrodynamic size of factors accumulating in systemic tissues.
Conclusions:
- Tumor vascular remodeling may redirect organism-wide signaling by tumor-derived factors.
- Altered factor bioavailability may negatively contribute to disease progression.
- Findings suggest implications for pre-metastatic niche formation and anti-tumor immunity regulation.
