From the Guest Editor: Illuminating Cancer In Vivo With Molecular Imaging.

Abstract

Genomic lesions within incipient cancer cells in collaboration with alterations in the microenvironment contribute to neoplastic progression. Tumor cells modulate the surrounding microenvironment to promote the progression of cancer through intrinsic oncogenic pathways. Furthermore, key genetic lesions have a profound impact on cancer cell migration, invasion, and regulation of the immune system through tumor-extrinsic manipulation of the microenvironment. The importance of the host microenvironment in neoplastic progression, independent of tumor manipulation, is also underscored by studies demonstrating that fibroblasts, other stromal cell types, and various immune cells stimulate growth of preneoplastic and neoplastic cells along with promoting drug resistance. Similarly, senescent fibroblasts promote preneoplastic cell growth in vitro and in vivo, and the stromal compartment also undergoes age-related changes in mutational load. Cell signaling networks enable cells to communicate and respond to changes in the microenvironment through signaling proteins that initiate a series of biochemical reactions within the cell. At any given time, a cell experiences numerous signals, initiating and integrating across multiple signal transduction pathways, and these signaling networks change spatially and temporally over the lifespan of a cell, resulting in heterogeneous cell populations with differing, and often transient, phenotypes. Importantly, many cell-to-cell–mediated signaling events arise in a tissue-restricted manner, and we now understand that protein-protein interactions, signal transduction, and gene expression are context specific. For example, the functional consequences of a given gene expressed during development can be quite different when the same gene is expressed in the adult, as seen with embryonic genes that are re-expressed in cancer cells. Understanding how cells communicate locally and globally in the context of a living organism has and will continue to yield breakthroughs in our understanding of cancer systems biology and hopefully enhance and expedite the drug development and discovery process. Given these observations, understanding the complex interactions between genomic lesions and tumor microenvironment is crucial to discovery of a greater understanding of tumorigenesis and new anticancer therapies. Thus, there is increasing need for studies of the genetic and molecular basis of cancer to migrate to the whole organism to correctly capture relevant molecular mechanisms in the proper context. Molecular imaging provides one such platform for noninvasive analysis of cancer biology in vivo. This set of molecular probes, detection technologies, and imaging strategies, collectively termed molecular imaging, now provides researchers and clinicians alike new opportunities to visualize gene expression, biochemical reactions, signal transduction, protein-protein interactions, regulatory pathways, cell trafficking, and drug action noninvasively and repetitively in their normal physiological context within living organisms in vivo. Molecular imaging techniques (nuclear, magnetic resonance, fluorescence, and bioluminescence) at both macroscopic and microscopic scales make it possible to explore tumor progression in vivo, in real time. New molecular probes, contrast agents, magnetic resonance hyperpolarization, exploitation of fundamental tissue characteristics, and development of multispectral fluorescent and bioluminescent (luciferase) proteins coupled with highly sensitive instrumentation have revolutionized noninvasive and longitudinal imaging of cancer biology at the whole organism level. These various molecular imaging modalities and strategies acquire macroscopic information in vivo through two basic strategies: injected agents or genetically encoded reporters. Injected agents have contributed significantly to preclinical cancer research and also have great potential for translation, but require significant optimization and characterization, depending on the experimental model, biological target, background noise, instrumentation, and route of administration, and, for human use, are impacted by similar regulatory hurdles as therapeutic agents. An inherent constraint to the development of conventional injectable agents is that the details of synthesizing, labeling, and validating a new and different ligand for every new receptor or protein of interest impose long cycle times on development.