On In Vivo Imaging in Cancer

At any one moment, >500,000 proteins are present within a human cell. Imaging techniques can capture complex molecular mechanisms, including those involved in cancer, in their normal physiological context.There are ∼23,500 genes in every human cell, but it is estimated that >500,000 proteins are present within the cell at any one moment, and 80% of these reside in protein heterocomplexes. Many proteins are altered by posttranslational modifications that impact subcellullar location, protein activity, protein-binding partners, and organellar trafficking. All of this complexity impacts gene expression and cell function. Importantly, many protein interactions arise following cell-to-cell signaling 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 being expressed during development can be quite different from those when the same gene is expressed in the adult, as seen with embryonic genes that are reexpressed in cancer cells (Monk and Holding 2001). Indeed, it can be stated with confidence that cell autonomous genetic changes within an incipient cancer cell in collaboration with alterations in the microenvironment contribute to neoplastic progression. This concept was not always appreciated, but is now widely accepted following the pioneering work of Mina Bissell and others (Novak 2005). The importance of the microenvironment in neoplastic progression is underscored by studies demonstrating that fibroblasts isolated from a tumor stimulate growth of preneoplastic and neoplastic cells in xenograft models. Gene expression patterns in cancer-associated fibroblasts are reminiscent of that found within a wound and include expression of numerous growth factors, chemokines, and angiogenic factors (Bissell and Radisky 2001), which suggests that the inflammatory response plays a key role in tumorigenesis. Similarly, senescent fibroblasts promote preneoplastic cell growth in vitro and in vivo (Pazolli et al. 2009), and the stromal compartment also undergoes age-related changes in mutational load.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 new set of molecular probes, detection technologies, and imaging strategies, collectively termed molecular imaging, now provides researchers and clinicians alike with 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 (Singer et al. 2005; Villalobos et al. 2007; Weissleder and Pittet 2008; Dothager et al. 2009).In particular, integration of genetically encoded imaging reporters into live cells and small animal models of cancer has provided powerful tools to monitor cancer-associated molecular, biochemical, and cellular pathways in vivo (Gross and Piwnica-Worms 2005). New animal models combined with imaging techniques (nuclear, fluorescence, and bioluminescence) at both macroscopic and microscopic scales will make it possible to explore the consequences of the interactions between tumor cells and microenvironment during tumor progression and between stromal cells and normal epithelial cells during normal morphogenesis in vivo in real time. Novel injectable agents under development that target key activities may someday enable investigators and clinicians to visualize these processes in patients.Condeelis and Weissleder (2011) review many of the principles and strategies for molecular imaging that will introduce the general reader to this exciting area of context-specific visualization of cancer biology in vivo.