Tissue Engineered Cancer Models for in vitro Recapitulation of the Native Tumor Microenvironment

Abstract

Despite having been first documented over 5000 years ago, cancer remains one of the most prevalent and lethal diseases to plague the human race to date. According to the National Cancer Institute, nearly half of Americans will be diagnosed with cancer during his or her lifetime, while the global incidence of cancer is projected to reach 21 million new cases diagnosed annually within the next decade. Thus, it has become exceedingly critical that highly-effective anti-cancer therapeutics be expeditiously developed and made clinically available. However, the current likelihood of approval for experimental oncology drugs entering clinical trials is only 5.1%. This poor performance can be partially attributed to the lack of a preclinical therapeutic testing platform that recapitulates the complex tumor microenvironment in vitro, and accurately predicts drug behavior in the human body. Through the amalgamation of recent advancements in novel biomaterial synthesis and cancer cell biology, this study reports the development of a physiologically relevant in vitro bioengineered tumor tissue model that transcends the limitations of conventional two-dimensional, cell aggregate, or murine model platforms. Bioengineered tumor tissues were fabricated utilizing poly(ethylene glycol) based hydrogels, functionalized with denatured fibrinogen to support cell adhesion and cell-mediated remodeling of the polymer matrix milieu. A myriad of experiments were performed to characterize encapsulated cell behavior and validate the potential utility of the model to bridge the translational gap between preclinical and clinical trials. Chapter 1 elucidates tumorigenic progression and reviews the current state of drug development processes and the cancer tissue engineering field. Chapter 2 reports the development and subsequent characterization of a bioengineered prostate tumor tissue model utilizing two prostate cancer cell lines in coculture with stromal fibroblasts. Chapter 3 presents a novel in vivo-in vitro tumor stiffness comparison study and investigates the effect of matrix stiffness on encapsulated prostate tumor cell behavior. Chapter 4 expounds the utility of the bioengineered tumor tissue model in personalized medicine and its ability to preserve cell populations of interest derived from colorectal cancer patient-derived xenograft tumors. Finally, the recommended future directions of the study are delineated, including extension to a notable microfluidic tumor-on-a-chip platform.