Molecular and Functional MRI of the Tumor Microenvironment

In malignant tumors, cancer cells are embedded within a complex microenvironment consisting of the extracellular matrix (ECM), blood and lymphatic vessels, infiltrating leukocytes, fibroblasts, and other stromal cells. This microenvironment is characterized by abnormal physiologic conditions such as hypoxia and acidic extracellular pH, generated largely by the chaotic tumor vasculature and lack of well-established lymphatics. Cancer cells can significantly contribute to this abnormal tumor microenvironment (TME) through increased glycolysis, upregulation of inflammatory pathways, and the secretion of proteolytic enzymes (1). Because several characteristics of the cancer cell are influenced by the interactions between cancer cells and the TME, the TME is increasingly occupying center stage in cancer etiology, progression, and response to treatment. Because of the remarkable ability of cancer cells to adapt and survive, finding effective treatments against cancer depends on identifying and targeting pathways critical for the survival of the cancer cells. Understanding and characterizing the TME provide unique opportunities to identify novel targets for cancer therapy. Multimodality and multiparametric molecular and functional imaging provide opportunities for imaging the TME and its interactions with cancer cells. magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) have traditionally been used to characterize functional tumor parameters such as pH, vascularization, and metabolism (2). The abundant water signal is typically used to obtain MR images with high spatial resolution. The magnetization signal is characterized by 2 rate constants, the spin–lattice (longitudinal relaxation time), or T1, and the spin–spin (transverse relaxation time), or T2. Most contrast agents used in MRI generate contrast or are detected by the changes they induce in the T1 or T2 of water. T1 contrast agents enhance the signal in a T1-weighted image, whereas T2 contrast agents result in a loss of signal in a T2-weighted image. MRS distinguishes a particular nucleus with respect to its environment in the molecule because the resonance frequency of a particular nucleus is dependent on its molecular structure. In MR spectroscopic imaging (MRSI), the chemical information is spatially encoded to obtain images of metabolites or exogenous substances or drugs. A major advantage of MRI techniques is that they can be translated from bench to bedside with relative ease, allowing repeated acquisition of spatial and temporal information. In this review, we have focused on some uses and advances of molecular and functional MRI techniques to image the TME.