Three-Dimensional Imaging and Quantification of Both Solitary Cells and Metastases in Whole Mouse Liver by Magnetic Resonance Imaging

Abstract

The metastatic cell population, ranging from solitary cells to actively growing metastases, is heterogeneous and unlikely to respond uniformly to treatment. However, quantification of the entire experimental metastatic cell population in whole organs is complicated by requirements of an imaging modality with the large field of view and high spatial resolution necessary to detect both single cells and metastases in the same organ. Thus, it is difficult to assess differential responses of these distinct metastatic populations to therapy. Here, we develop a magnetic resonance imaging (MRI) technique capable of quantifying the full population of metastatic cells in a secondary organ. B16F1 mouse melanoma cells were labeled with micron-sized iron oxide particles (MPIO) and injected into mouse liver via the mesenteric vein. Livers were removed immediately or at day 9 or 11, following doxorubicin or vehicle control treatment, and imaged using a 3T clinical magnetic resonance scanner and custom-built gradient coil. Both metastases (>200 μm) and MPIO-labeled single cells were detected and quantified from MR images as areas of hyperintensity or hypointensity (signal voids), respectively. We found that 1 mg/kg doxorubicin treatment inhibited metastasis growth (n = 11 per group; P = 0.02, t test) but did not decrease the solitary metastatic cell population in the same livers (P > 0.05). Thus, the technique presented here is capable of quickly quantifying the majority of the metastatic cell population, including both growing metastases and solitary cells, in whole liver by MRI and can identify differential responses of growing metastases and solitary cells to therapy. [Cancer Res 2009;69(21):8326-31]

β1-Integrin: A Potential Therapeutic Target in the Battle against Cancer Recurrence

“…Resistance of dormant solitary cells to chemotherapy has been shown previously in vivo (3,8,28) and in the 3D model system (D. Barkan; unpublished data). This resistance is due to the quiescent nature of the dormant cells.…”

“…Several experimental mouse metastasis models using a variety of cancer cell lines showed the presence of dormant cancer cells, often coexisting in a metastatic site with actively growing metastases (1)(2)(3)(4)(5)(6)(7)(8)(9). Furthermore, these 2 populations of cells have been shown to be biologically distinct, with, for example, very different responses to cytotoxic chemotherapy (2,3,10).…”

Brain metastases from breast cancer: lessons from experimental magnetic resonance imaging studies and clinical implications

“…This phenomenon presents a significant treatment challenge because its biology deviates from traditional understanding of malignant cancer growth. Current chemotherapies target highly proliferating cells and therefore dormant cells persist unaffected [22,23].…”

The synthetic triterpenoid CDDO-Imidazolide suppresses experimental liver metastasis

“…The heterogeneous nature of the metastatic cell population makes it unlikely that all cells will respond uniformly to treatment. This situation has been demonstrated in experimental metastasis model in which doxorubicin significantly inhibited the growth of large actively growing metastases, but had no effect on the number and viability of solitary cells or their ability to form late occurring metastases following treatment [29,30]. Thus, new therapies should be tested for their effects on both sub-populations of metastatic cells, those that are actively proliferating and those that are dormant, in order to better understand and use new treatments.…”