Radiotherapy and chemotherapy change vessel tree geometry and metastatic spread in a small cell lung cancer xenograft mouse tumor model

Abstract

BackgroundTumor vasculature is critical for tumor growth, formation of distant metastases and efficiency of radio- and chemotherapy treatments. However, how the vasculature itself is affected during cancer treatment regarding to the metastatic behavior has not been thoroughly investigated. Therefore, the aim of this study was to analyze the influence of hypofractionated radiotherapy and cisplatin chemotherapy on vessel tree geometry and metastasis formation in a small cell lung cancer xenograft mouse tumor model to investigate the spread of malignant cells during different treatments modalities.MethodsThe biological data gained during these experiments were fed into our previously developed computer model “Cancer and Treatment Simulation Tool” (CaTSiT) to model the growth of the primary tumor, its metastatic deposit and also the influence on different therapies. Furthermore, we performed quantitative histology analyses to verify our predictions in xenograft mouse tumor model.ResultsAccording to the computer simulation the number of cells engrafting must vary considerably to explain the different weights of the primary tumor at the end of the experiment. Once a primary tumor is established, the fractal dimension of its vasculature correlates with the tumor size. Furthermore, the fractal dimension of the tumor vasculature changes during treatment, indicating that the therapy affects the blood vessels’ geometry. We corroborated these findings with a quantitative histological analysis showing that the blood vessel density is depleted during radiotherapy and cisplatin chemotherapy. The CaTSiT computer model reveals that chemotherapy influences the tumor’s therapeutic susceptibility and its metastatic spreading behavior.ConclusionUsing a system biological approach in combination with xenograft models and computer simulations revealed that the usage of chemotherapy and radiation therapy determines the spreading behavior by changing the blood vessel geometry of the primary tumor.

The initial engraftment of tumor cells is critical for the future growth pattern: a mathematical study based on simulations and animal experiments

“…Typically, the variations between groups in the mean values of primary tumor size measured on different days are considered to be indicators of differences in, for example, the effectiveness of a drug treatment [3][4][5][6]. Sometimes data from these experiments are fitted to mathematical growth functions to describe and predict the growth of the tumor [7][8][9]. This experimental procedure promises well-defined reproducible results and generates new insights into metastasis formation when mathematical modeling is applied [10].…”

Engineered Polymeric Materials for Biological Applications: Overcoming Challenges of the Bio–Nano Interface

“…The role of vascular endothelial growth factor (VEGF) in these processes has resulted in it becoming an attractive target for accumulation at the tumor site [88,100]. Co-delivery of vessel normalizing drugs, vasodilators, and remodeling of the cancer-associated vasculature have also become prominent approaches to improving the accumulation of nanomaterials at the tumor site, with varying levels of success reported [101,102,103].…”

“…In terms of delivering nanomedicines across the endothelial barrier, a number of methods have been developed to improve the rate of extravasation and thus accumulation within the tumor mass. Recent efforts have demonstrated that the EPR effect may be improved through altering blood vessel geometry [102], normalizing vasculature [101], remodeling [103], and vessel pruning [123]. Microbubble cavitation can also be used to disrupt endothelial barriers and increase flow of material from vasculature into the tumor mass [124].…”

Inter-Metastatic Heterogeneity of Tumor Marker Expression and Microenvironment Architecture in a Preclinical Cancer Model

“…This means that in a metastatic setting, the organ/tissue that permits cancer cell seeding and growth likely plays a significant role in the vascular microenvironment, and consequently could impact drug delivery, distribution, and efficacy [42][43][44][45][46][47][48][49][50]. (iii) Treatments can affect vessel growth, structure, and function, adding to the complexity of vascular heterogeneity, which will change as a function of time after treatment is initiated [51,52]. Regardless of the root cause of vascular heterogeneity (i.e., location of disease burden or therapeutic implications), when evaluating a drug candidate's ability to reach and penetrate within a given tumor, at the very least, the vessel microenvironment must be considered, and it is insufficient to investigate in the context of just one site of tumor growth if the goal is to obtain meaningful therapeutic results in late-stage patients.…”