Imaging pH and metastasis

Abstract

Metastasis is a multistep process that culminates in the spread of cells from a primary tumor to a distant site or organs. For tumor cells to be able to metastasize, they have to locally invade through basement membrane into the lymphatic and the blood vasculatures. Eventually they extravasate from the blood and colonize in the secondary organ. This process involves multiple interactions between the tumor cells and their microenvironments. The microenvironment surrounding tumors has a significant impact on tumor development and progression. A key factor in the microenvironment is an acidic pH. The extracellular pH of solid tumors is more acidic in comparison to normal tissue as a consequence of high glycolysis and poor perfusion. It plays an important role in almost all steps of metastasis. The past decades have seen development of technologies to non-invasively measure intra- and/or extracellular pH. Most successful measurements are MR-based, and sensitivity and accuracy have dramatically improved. Quantitatively imaging the distribution of acidity helps us understand the role of the tumor microenvironment in cancer progression. The present review discusses different MR methods in measuring tumor pH along with emphasizing the importance of extracelluar tumor low pH on different steps of metastasis; more specifically focusing on epithelial-to-mesenchymal transition (EMT), and anti cancer immunity.

Figure 1. Stages of Metastasis

Primary carcinomas arise from epithelia which face ductal lumens and are separated from stroma by a basement membrane. After disruption of basement membrane integrity the locally invasive cells gain access to lymphatic- and heme-vasculature wherein they form circulating tumor cells, CTCs. At secondary sites (right) the tumor cells extravasate into parenchyma, where they colonize and become vascularized either through co-option or neo-angiogenesis (reprinted by permission. Scientific American.)

Figure 2. pHe and pHi of tumors and normal tissues by 31P MRS of 3-APP and Pi respectively

Subsequent measurements have shown unequivocally that the pHe of tumor xenografts is acidic, whereas the pHi is neutral-to-alkaline.

Figure 3. pHe map of breast cancer xenograft

MDA-mb-435 flank tumors were infused with IEPA and pH was measured by 1H MRS.

Figure 4

In vivo tumor pHe maps were generated using relaxivity-based single injection method, a combination of T1-weighted imaging and spectroscopic imaging in a C6 rat glioma model. A1 and B1 shows T1-W contrast enhancement after CA infusion in two different animals. A2 and B2 are the corresponding tumor pHe maps.

Figure 5. Measurement of metastasis in vivo and in vitro

Experimental Metastases in Intravenous Model - SCID-beige injected with5×10 6 of PC-3M-luc-C6 cells. A. Lung signals are visible after cell injection on day 0. Signals drop as lungs clear between day 1 to week 2. Metastatic signals reappear in week 3-4 and all mice develop multiple signals by week 5. B. Ex vivo imaging confirms metastases in bone and lungs. C. tumor bioluminescence expressed as photons/sec.