Cancer Biology of Molecular Imaging

Abstract

Cancer is a complex series of stepwise genetic mutations and epigenetic modifications resulting in characteristic phenotypic changes in the transformed neoplastic cells (“cancer hallmarks”). Some of the altered genes become “oncogenes,” a gene whose presence induces a cascade of biologic events that promote malignant transformation of the cell, causing unchecked proliferation and spread (metastases) widely in the body with the potential to disrupt and even destroy the normal tissue phenotype; this leads to loss of essential normal functions and ultimately, if not effectively treated, death of the host. Locally, at both primary and metastatic sites, cancer cells recruit normal host tissues to create a favorable environment for their survival and replication. Fibrocytes and collagen-producing cells provide structure for the tumor cells to form a stroma, also called tumor microenvironment (TME). Cancer cells interact with this stroma through paracrine signals that alter the stromal phenotype to be maximally supportive of the tumor mass. Endothelial cells are recruited to form blood vessels prompting tumor blood flow, providing oxygen and nutrients for growth. Tumor blood vessels have incomplete endothelium, making the vessels leaky. This allows large molecules and immune cells to pass readily into the tumor interstitium, often fostering an environment within the mass that resists immunologic attack.

Hallmarks of cancer include rapid proliferation, a characteristic metabolism, immortality, resistance to apoptosis, resistance to suppression of proliferation, metastatic behavior, and resistance to immunologic attack. There is growing evidence that the individual cellular phenotype in cancers is continuously evolving based on epigenetic action (“lineage plasticity”), during which multiple genes may be co-opted from usually quiescent tissue development pathways. These changes sometimes promote intrinsic and extrinsic resistance to cancer treatments. The tumor mass may locally invade surrounding tissue, causing pain and organ dysfunction. Cells and groups of cells leave the primary mass as single cells or in clusters and metastasize to distant organs, often in an organ selective manner.

Molecular imaging (MI) and its therapeutic twin molecular targeted radiotherapy (MTR) are rapidly evolving into major determinants for diagnostic and treatment decisions in clinical oncology. Molecular imaging offers quantitative detection of the molecules and molecular-based events that are fundamental to the malignant state in vivo in living subjects. MTR exploits the unique biochemical specificity of cancer-related molecular targets to deliver focused radiation to cancer cells. In this chapter, we shall learn how the discovery of key biomolecules and biochemical processes central to cancer genesis and progression are being mirrored in successful development of practical diagnostic and therapeutic radiopharmaceuticals useful for clinical care.

These advances in available radiodrugs occur in the context of the ever-expanding capability of nuclear imaging methods, with improved resolution, sensitivity, and quantitative power that permits real-time functional imaging at the tumor and tissue level. Clinical PET and SPECT imaging is now “fusion” imaging, whereby an anatomic context comes directly from high-resolution cross-sectional imaging equipment, particularly CT and MRI; fusion images facilitate staging and treatment response monitoring for oncology. Additionally, high-speed computer-based analytic platforms convert radioactive counts into functional images representing key tumor-specific biochemical processes.