Abstract
Simple SummaryBoron neutron capture therapy (BNCT) is becoming one of the most promising radiotherapies for aggressive cancers, but the detailed cellular mechanisms of BNCT remain largely underexplored. Solid tumors are composed of heterogeneous cell populations, which create a 3-dimensional complicated microenvironment for tumor progression. To recapture the influences of the microenvironment on BNCT efficacy, we applied a self-assembly 3D cell culture system with two different types of pancreatic cancer cells. In contrast to previous findings with γ-ray exposure, we found that the 3D architecture of pancreatic tumor can facilitate the susceptibility of cancer cells to BNCT, as compared to 2D tissue structure; a computer simulation model was established to further confirm this unexpected finding. These outcomes can contribute to better understanding of the radiobiology of BNCT, and the developed models may facilitate the recent development in personalized radiotherapy.Pancreatic cancer is a leading cause of cancer death, and boron neutron capture therapy (BNCT) is one of the promising radiotherapy techniques for patients with pancreatic cancer. In this study, we evaluated the biological effectiveness of BNCT at multicellular levels using in vitro and in silico models. To recapture the phenotypic characteristic of pancreatic tumors, we developed a cell self-assembly approach with human pancreatic cancer cells Panc-1 and BxPC-3 cocultured with MRC-5 fibroblasts. On substrate with physiological stiffness, tumor cells self-assembled into 3D spheroids, and the cocultured fibroblasts further facilitated the assembly process, which recapture the influence of tumor stroma. Interestingly, after 1.2 MW neutron irradiation, lower survival rates and higher apoptosis (increasing by 4-fold for Panc-1 and 1.5-fold for BxPC-3) were observed in 3D spheroids, instead of in 2D monolayers. The unexpected low tolerance of 3D spheroids to BNCT highlights the unique characteristics of BNCT over conventional radiotherapy. The uptake of boron-containing compound boronophenylalanine (BPA) and the alteration of E-cadherin can partially contribute to the observed susceptibility. In addition to biological effects, the probability of induced α-particle exposure correlated to the multicellular organization was speculated to affect the cellular responses to BNCT. A Monte Carlo (MC) simulation was also established to further interpret the observed survival. Intracellular boron distribution in the multicellular structure and related treatment resistance were reconstructed in silico. Simulation results demonstrated that the physical architecture is one of the essential factors for biological effectiveness in BNCT, which supports our in vitro findings. In summary, we developed in vitro and in silico self-assembly 3D models to evaluate the effectiveness of BNCT on pancreatic tumors. Considering the easy-access of this 3D cell-assembly platform, this study may not only contribute to the current understanding of BNCT but is also expected to be applied to evaluate the BNCT efficacy for individualized treatment plans in the future.
Highlights
Pancreatic cancer is the third leading cause of death from cancer in the United States [1]
A higher apoptotic response of BxPC-3 was noted in 3D spheroids than in 2D monolayers, the increase was only 44% higher than in 2D cells. These findings suggest that the pancreatic cancer cells in 3D spheroids were more sensitive to the boron neutron capture therapy (BNCT) treatment than those in the conventional 2D culture; the fibroblast cells, in our experimental conditions, had no influence on cell Cancers 2021, 13, x FOR PEER REVIEvWiability or apoptosis
Because the intracellular distribution of 10B within tumors influences the Relative biological effectiveness (RBE) of BNCT treatment [33], we examined the difference in BPA uptake bbeettwweeeenn33DDsspphheerrooiiddssaanndd22DDmmoonnoolalayyeerrssbbyyuussininggIICCPP--MMSS. .FFoorrththeePPaanncc-1-1cceelllsls,hhigighheerr BBPPAAuupptatakkeewwaassoobbsseerrvveeddininththee33DDsspphheerrooididssththaannininththee22DDmmoonnoolalayyeerrss; ;nnoossigignnifiifcicaanntt ddiiffffeerreenncceewwaass oobbsseerrvveedd bbeettwweeeenn 22DD aanndd33DDPPaanncc-1-1ccuultluturerecoconndditiitoionns sininthteheprperseesnecnecoef offibfirbobrolabsltas(Ft i(gFuigreur3ea)3.aF).orFBoxrPBCx-P3Cc-e3llcs,elllosw, leorwBePrABPuAptaukpeta(kbey 0w%a)s woabsseorbvseedrvined3Dins3pDhesrpohiderso, iadnsd, athnedpthreespenrecseeonfcfeiborfofibblarostbfluasrtthfeurrtrheedrurceedduBcPedABuPpAtaukpet(aFkige(uFirgeu3rbe).3b)
Summary
Pancreatic cancer is the third leading cause of death from cancer in the United States [1]. The treatment of pancreatic cancer remains challenging, and the average 5-year survival rate for people with pancreatic cancer is only 10% [4]. More than 50% of patients with cancer receive radiation therapy. An emerging topic in radiation oncology is the development of high-energy particles for tumor treatment [8]. Boron neutron capture therapy (BNCT), which uses the limited path length (5–9 μm) of high linear energy transfer particles and recoiling lithium, generated when thermal neutrons are incident on boron-10, can selectively destroy tumor cells with minimal injury to non-cancer tissue [9]. The promising efficacy of BNCT for recurrent malignant gliomas and head and neck cancers has been reported in clinical studies [11], the potency of BNCT for pancreatic cancer treatment has not been fully explored
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