Robert J. Gillies

Coevolution of Tumor Cells and Their Microenvironment: “Niche Construction in Cancer”

Abstract Cancer is a complex, adaptive, and dynamic system, made up of cancer cells interacting with an ever-changing microenvironment. Interactions among components of the cancer system over time and space are often multiscalar and typically nonlinear. Each transition, such as expression of a new gene product, is governed by a cell’s content and history as well as local microenvironmental properties and selection forces. Hence, cancer is an open system, as it freely interacts with the local host tissue. This permits normal tissue to affect tumor but also allows tumor populations to alter the local environment in ways that promote tumor growth—an adaptive strategy termed “niche construction.” Because these dynamic interactions between the host and the tumor are both complex and nonlinear, even subtle perturbations of the environment can have profound effects on the tumor. Here we focus on the tumor–host interactions that give rise to metabolic heterogeneity, which includes the following: (1) tumor oxygenation, governed by variations in delivery due to temporal and spatial heterogeneity in blood flow, which in part is governed by tumor-derived angiogenic factors; and (2) tumor extracellular pH (pHe), governed by both blood flow and upregulation of fermentative glucose pathways in regions of hypoxia and normoxia, known as aerobic glycolysis (i.e., the Warburg effect; see subsequent text), which aids the tumor by blunting the immune response and promoting invasive growth. Importantly, these dynamics can be exploited or manipulated to treat tumors. For example, tumor cells in regions of low oxygen can be targeted with specific hypoxia-activated prodrugs. Similarly, blood flow can be altered with antiangiogenesis drugs and tumor cells in acidic regions can be targeted by specific metabolic inhibitors and buffer therapies. Furthermore, these metabolic factors can significantly affect the coevolution of cancers with the innate and adaptive immune systems. Here we focus on the complex and dynamic interactions between the microenvironmental factors and tumor cells, and their impact on carcinogenesis and metastasis.

Radiomic biomarkers from PET/CT multi-modality fusion images for the prediction of immunotherapy response in advanced non-small cell lung cancer patients.

Purpose: Investigate the ability of using complementary information provided by the fusion of PET/CT images to predict immunotherapy response in non-small cell lung cancer (NSCLC) patients. Materials and methods: We collected 64 patients diagnosed with primary NSCLC treated with anti PD-1 checkpoint blockade. Using PET/CT images, fused images were created following multiple methodologies, resulting in up to 7 different images for the tumor region. Quantitative image features were extracted from the primary image (PET/CT) and the fused images, which included 195 from primary images and 1235 features from the fusion images. Three clinical characteristics were also analyzed. We then used support vector machine (SVM) classification models to identify discriminant features that predict immunotherapy response at baseline. Results: A SVM built with 87 fusion features and 13 primary PET/CT features on validation dataset had an accuracy and area under the ROC curve (AUROC) of 87.5% and 0.82, respectively, compared to a model built with 113 original PET/CT features on validation dataset 78.12% and 0.68. Conclusion: The fusion features shows better ability to predict immunotherapy response prediction compared to individual image features.

Chapter 4 – Pseudohypoxia: Life at the Edge

“Pseudohypoxia” is a process wherein cells express hypoxia (i.e., low oxygen)-associated proteins, regardless of the oxygen status. Notably, this phenotype is often observed at the tumor–stromal interface in locally invading tumors. This may be an important feature of tumor physiology, and is being corroborated by mathematical modeling and clinical histology. Until now, little attention has been given to the physiology of the tumor–stromal interface. We propose that pseudohypoxia at the invasive edge provides an evolutionary fitness advantage for tumors that becomes selected during clonal expansion within the tumor. Pseudohypoxic cells are more aggressive, acid producing, and glycolytic, due to upregulation of proteins, such as glucose transporter 1 (GLUT-1) and carbonic anhydrase nine (CA-IX). Investigation of this phenotype is untapped, and may lead to a deeper understanding of basic tumor physiology and potentially illuminate targets that could disrupt this vitally important tumor survival system.