Influence of Radiotherapy Fractionation Schedule on the Tumor Vascular Microenvironment in Prostate and Lung Cancer Models

Abstract

Background. The tumor vasculature acts as an interface for the primary tumor. It regulates oxygenation, nutrient delivery, and treatment efficacy including radiotherapy. The response of the tumor vasculature to different radiation doses has been disparately reported. Whereas high single doses can induce endothelial cell death, improved vascular functionality has also been described in a various dose range, and few attempts have been made to reconcile these findings. Therefore, we aimed at comparing the effects of different radiation fractionation regimens on the tumor vascular microenvironment. Methods: Lewis lung and prostate PC3 carcinoma-derived tumors were irradiated with regimens of 10 × 2 Gy, 6 × 4 Gy, 3 × 8 Gy or 2 × 12 Gy fractions. The tumor vasculature phenotype and function was evaluated by immunohistochemistry for endothelial cells (CD31), pericytes (desmin, α-SMA), hypoxia (pimonidazole) and perfusion (Hoechst 33342). Results: Radiotherapy increased vascular coverage similarly in all fractionation regimens in both models. Vessel density appeared unaffected. In PC3 tumors, hypoxia was decreased and perfusion was enhanced in proportion with the dose per fraction. In LLC tumors, no functional changes were observed at t = 15 days, but increased perfusion was noticed earlier (t = 9–11 days). Conclusion: The vascular microenvironment response of prostate and lung cancers to radiotherapy consists of both tumor/dose-independent vascular maturation and tumor-dependent functional parameters.

Radiation dose and fraction in immunotherapy: one-size regimen does not fit all settings, so how does one choose?

“…72 On the other spectrum, hypofractionated radiation causes vascular remodeling, affected diffusion and influences hypoxia. 82 Dose escalation of radiotherapy may also optimize the induction of immunogenic tumor cell death 83 84 and increase expression of pro-immune markers such as major histocompatibility complex class I. 62 85 Recent mechanistic studies also shed light on negative feedback Open access pathways that may antagonize the immunogenic effects of radiation at high doses (20 Gy) but not at moderate fractional doses (8-12 Gy).…”

Exosomal miRNAs in tumor microenvironment

“…Hypoxia caused by rapid appreciation of tumor cells leads to release of matrix metalloproteinases (MMPs), hypoxia inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF) and other stimulating factors. Reshaping TME provides a niche for interaction between tumor cells and surrounding fibroblasts, endothelial cells, and immune cells [4,[6][7][8][9]. These cells interact with tumor cells through TME to induce a variety of biological events, such as appreciation, migration, angiogenesis, immunosuppression, and drug resistance for tumor development [10][11][12][13][14].…”

Granulocyte Colony Stimulating Factor Expression in Breast Cancer and Its Association with Carbonic Anhydrase IX and Immune Checkpoints

“…Non-luminal breast cancers are known to rely on an active NF-κB signalling pathway; it is therefore plausible that this relationship exists in clinical samples to a certain degree [ 60 , 61 ]. Furthermore, several studies have described a role of G-CSF in tumour progression using the same hypoxic, CAIX-expressing 4T1 model [ 62 , 63 , 64 ] or additional models containing significant levels of hypoxia such as Lewis lung carcinoma [ 65 ] and MMTV-PyMT [ 66 ], suggesting a critical role of hypoxia in regulating G-CSF biology in these models. Importantly, cytokine networks in the hypoxic tumour microenvironment, including those orchestrated by TGF-β, may cooperate with G-CSF to potentially influence neutrophil polarization [ 67 ].…”