Malignant transformation of tumor accompanies profound changes in the normal neighboring tissue, called tumor stroma. The tumor stroma provides an environment favoring local tumor growth, invasion, and metastatic spreading. Nuclear imaging (PET/SPECT) measures biochemical and physiologic functions in the human body. In oncology, PET/SPECT is particularly useful for differentiating tumors from postsurgical changes or radiation necrosis, distinguishing benign from malignant lesions, identifying the optimal site for biopsy, staging cancers, and monitoring the response to therapy. Indeed, PET/SPECT is a powerful, proven diagnostic imaging modality that displays information unobtainable through other anatomical imaging, such as CT or MRI. When combined with coregistered CT data, [18F]fluorodeoxyglucose ([18F]FDG)-PET is particularly useful. However, [18F]FDG is not a target-specific PET tracer. This paper will review the tumor microenvironment targeting oncologic imaging such as angiogenesis, invasion, hypoxia, growth, and homing, and also therapeutic radiopharmaceuticals to provide a roadmap for additional applications of tumor imaging and therapy. 1. Introduction The tumor stroma, consisting of cells, structural proteins, and signaling molecules, which includes fibroblasts/myofibroblasts, glial, epithelial (EC), fat, vascular, smooth muscle, and immune cells along with the extracellular matrix (ECM) and extracellular molecules, is playing a central role in tumor initiation, progression, and metastasis (Figure 1). Growth factor and chemokine production by fibroblasts and immune cells is altered, leading to direct stimulation of tumor cell growth and recruitment of precursor cells, which themselves respond with abnormal growth and proliferation [1]. The unique reciprocal act between the various aspects of the tumor and the microenvironment has been the recent target of molecular strategies for tumor treatment. Targeting the stroma poses several obstacles; however, the level of tumor aggression is greatly influenced by this environment, providing multiple targets for anticancer therapy. The cells associated with stroma are not malignant themselves, which demands successful therapy to aim at phenotypic changes unique to this population, while avoiding normal cells elsewhere. Additionally, malformed tumor vessels contribute to tumor hypoxia, acidosis, and increased interstitial fluid pressures which challenge the delivery of target agents to the stroma. Hence a successful approach requires identification of appropriate targets and efficient delivery methods.
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