MRI‐measured water mobility increases in response to chemotherapy via multiple cell‐death mechanisms

Abstract

Numerous pre-clinical and clinical reports have demonstrated that the MRI-measured apparent diffusion coefficient of water (ADC) increases early in the response to a wide variety of anti-cancer therapies. It has been proposed that this increase in ADC generally results from an increase in the tumor extracellular volume fraction leading to a greater degree of unrestricted water motion. Furthermore, an increase in extracellular volume has been ascribed to the cell shrinkage that occurs early in the process of programmed cell death. However, other modes of death can be initiated soon after beginning therapy. These other modes of death include mitotic catastrophe and necrosis, and may also involve changes in the fraction of water with unrestricted motion. This work examines whether MRI-measured ADC is altered in response to therapies that induce cell death via non-apoptotic mechanisms and correlates ADC changes with cell death modalities regionally within the tumor. Apoptotic responses were limited to the tumor periphery in apoptosis-proficient tumors. Apoptosis was not observed in deficient tumors. Mitotic catastrophe was observed after treatment at the periphery and deeper into the tumor. Necrosis was the predominant response in the center of the tumor. ADC changes were moderate in the periphery and larger in the center. The results indicate that early and significant changes in ADC can occur in concert with mitotic catastrophe and lytic necrosis in the absence of apoptosis. Hence, changes in ADC may be a generalized measure of cytotoxic response to chemotherapy.

Glycolytic Phenotype and AMP Kinase Modify the Pathologic Response of Tumor Xenografts to VEGF Neutralization

“…The apparent diffusion coefficient (ADC) value is often correlated with tumor cellularity, and in experimental tumors, an elevated ADC value has been correlated with the necrotic fraction (23 /s (mean AE SD) for the OC316 and IGROV-1 xenografts, respectively, which were in good agreement with those recently measured in patients with ovarian carcinoma (24). Short-course anti-VEGF treatment was associated with changes in spectral profiles and ADC distributions.…”

Role of the Apparent Diffusion Coefficient as a Predictor of Tumor Progression in Patients with Chordoma

“…RT might affect MR imaging signal evaluation in residual or recurrent tumors. [31][32][33] We did not find any correlation between the ADC values and RT dose or duration from RT to the first MR imaging (On-line Appendix). However, ADC values reflecting the response to treatment might be increased several days after RT or chemotherapy in various types of tumors.…”

“…However, ADC values reflecting the response to treatment might be increased several days after RT or chemotherapy in various types of tumors. [31][32][33][34] Given that ADC values correlate with cell density, 33 the treat- ment response (with reduction of tumor cell volume) could elevate the ADC, while tumor progression (with proliferation of tumor cells) could decrease it. There is little information concerning MR imaging signal changes in chordomas after RT, particularly after proton or carbon ion RT.…”

Molecular Imaging of Neurovascular Cell Death in Experimental Cerebral Stroke by PET

“…However, apoptotic cells in tissues are associated with the opposite phenomenon, that is, an increased ADC, because of a shift of water molecules from the intracellular space to the extracellular space. This apoptosis-related increased ADC is used, for example, in the monitoring of apoptosis induced by anticancer agents (25,26). Thus, a cerebral infarct is subjected to opposite ADC changes, leading to pseudonormalization of signals (27) and thus ruling out the use of DWI as a method for determining stroke-related apoptosis.…”