The goal of this study was to examine the use of diffusion-weighted magnetic resonance imaging (DW-MRI) for the assessment of early progression of photodamage induced by Pd-bacteriopheophorbide (TOOKAD)-based photodynamic therapy (PDT). TOOKAD is a novel second-generation photosensitizer for PDT of solid tumors developed in our laboratory and presently under clinical trials for prostate cancer (PC) therapy. Using the subcutaneous human prostate adenocarcinoma WISH-PC14 xenografts in nude mice as a model, a unique biphasic change in the apparent diffusion coefficient (ADC) was observed within the first 24 hours post-PDT, with initial decrease followed by an increase in ADC. Using DW-MRI, this phenomenon enables the detection of successful tumor response to PDT within 7 hours posttreatment. This process was validated by direct, histological, immunohistochemical examinations and also by evaluation of serum prostate-specific antigen (PSA) levels that decreased significantly already 7 hours posttreatment. In vitro studies of multicellular cell spheroids confirmed a PDT-induced decrease in ADC, suggesting that lipid peroxidation (LPO) significantly contributes to ADC decline observed after PDT. These results demonstrate that TOOKAD-based PDT successfully eradicates prostate adenocarcinoma xenografts and suggests DW-MRI to be useful for the detection of early tumor response and treatment outcome in the clinical setting.
<p>Supplementary figure 6 shows additional assessments of B cells in FL patient tissue samples and their activation status and supportive in vitro B cells findings.</p>
Abstract The major cause of cancer-associated mortality is metastasis, but our understanding of this process is far from complete. Tumor cells invade the surrounding tissue of the primary tumor, intravasate into blood and lymphatic vessels, survive and translocate to distant tissues, extravasate, adapt to the new microenvironment and eventually seed, proliferate and colonize to form metastases. Nearly 125 years ago, Paget enunciated the seed and soil hypothesis of cancer. More recently, emerging data suggested that the cellular and extracellular matrix (ECM) microenvironments—both in the primary tumor and in metastatic sites—are crucial at multiple stages of metastasis. Significantly, targeting the tumor microenvironment in metastasis might hold promise for therapy as stromal cells are not mutated and the effects may be widespread as the ECM interacts with multiple tumor cells. The ECM, which is a rich reservoir of pro- and anti-angiogenic cues that regulate neovascularization of the tumor, a crucial process in tumor cell dissemination. The developing metastatic lesions result from a complex crosstalk between disseminating tumor cells and the different players in the microenvironment of the metastatic lesion. The specific recruitment of distinct populations of leukocytes and stromal cells with overlapping functions in metastasis, may open new avenues to the development of metastasis-targeted therapies. Finally, the function of the tumor microenvironment in modulating sensitivity to chemotherapy is of clinical importance. But the aspects of the microenvironment contribute to loss of drug efficacy are still poorly understood in the metastatic setting. The microenvironment is an important source of anticancer drug resistance and also a therapeutic target, as drugs might not need to be completely penetrant to be effective because altering some immune cells, ECM components or the vasculature may have profound effects as seen with regulation of microRNAs. The microenvironment faced by cells at metastatic sites also determines whether these cells die, proliferate or become dormant. How does the microenvironment evolve from the pre-metastatic stage to established metastases? Determining whether the metastatic niche arises from changes in the ECM, decreased immune surveillance or changes in specific pro-inflammatory molecules poses a challenge for the future. We need a more complete understanding of the role of the metastatic microenvironment to uncover how these processes promote metastasis. Chou, J., J.H. Lin, A. Brenot, J.-w. Kim, S. Provot & Z. Werb (2013). GATA3 suppresses metastasis and modulates the tumor microenvironment by regulating miR-29 expression. Nat. Cell Biol. 15: 201-213. PMCID: PMC3660859. Egeblad, M., A. J. Ewald, H. A. Askautrud, B. E. Welm, M. Truitt, E. Bainbridge, G. Peeters, M. Krummell & Z. Werb (2008). Visualizing stromal cell dynamics in different tumor microenvironments by spinning disk confocal microscopy. Dis. Model. Mech. 1:155-167. PMCID: PMC2562195. Kessenbrock, K., G.J.P. Dijkgraaf, D. A. Lawson, L. E. Littlepage, P. Shahi, U. Pieper & Z. Werb (2013). A role for matrix metalloproteinases in regulating mammary stem cell function via the Wnt signaling pathway. Cell Stem Cell. 13:300-313. PMCID: PMC3769456. Lu, P., V. M. Weaver & Z. Werb (2012). Extracellular matrix: a dynamic niche component during cancer progression. J. Cell Biol. 196:396-406. PMCID: PMC3283993. Nakasone, E., H. A.Askautrud, T. Kees, V. Plaks, A. J. Ewald, M. G. Rasch, Y. X. Tan, J. Qin, M. Fein, J. Park, P. Sinha, M. J. Bissell, E. Frengen, Z. Werb & M. Egeblad (2012). Imaging tumor-stroma interactions during chemotherapy reveals microenvironmental contributions to chemoresistance. Cancer Cell. 21:488-503. PMCID: PMC3332002. Citation Format: Amy-Jo Casbon, Vicki Plaks, Zena Werb. Building the metastatic microenvironment. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr IA09. doi:10.1158/1538-7445.CHTME14-IA09
WST11 is a novel negatively charged water-soluble palladiumbacteriochlorophyll derivative that was developed for vascular-targeted photodynamic therapy (VTP) in our laboratory. The in vitro results suggest that WST11 cellular uptake, clearance and phototoxicity are mediated by serum albumin trafficking. In vivo, WST11 was found to clear rapidly from the circulation (t1/2 5 1.65 min) after intravenous bolus injection in the mouse, whereas a longer clearance time (t1/2 5 7.5 min) was noted in rats after 20 min of infusion. The biodistribution of WST11 in mouse tissues indicates hepatic clearance (t1/2 5 20 min), with minor (kidney, lung and spleen) or no intermediary accumulation in other tissues. As soon as 1 h after injection, WST11 had nearly cleared from the body of the mouse, except for a temporal accumulation in the lungs from which it cleared within 40 min. On the basis of these results, we set the VTP protocol for a short illumination period (5 min), delivered immediately after WST11 injection. On subjecting M2R melanoma xenografts to WST11-VTP, we achieved 100% tumor flattening at all doses and a 70% cure with 9 mg/kg and a light exposure dose of 100 mW/cm 2 . These results provide direct evidence that WST11 is an effective agent for VTP and provide guidelines for further development of new candidates.
The goal of this study was to examine the use of diffusion-weighted magnetic resonance imaging (DW-MRI) for the assessment of early progression of photodamage induced by Pd-bacteriopheophorbide (TOOKAD)-based photodynamic therapy (PDT). TOOKAD is a novel second-generation photosensitizer for PDT of solid tumors developed in our laboratory and presently under clinical trials for prostate cancer (PC) therapy. Using the subcutaneous human prostate adenocarcinoma WISH-PC14 xenografts in nude mice as a model, a unique biphasic change in the apparent diffusion coefficient (ADC) was observed within the first 24 hours post-PDT, with initial decrease followed by an increase in ADC. Using DW-MRI, this phenomenon enables the detection of successful tumor response to PDT within 7 hours posttreatment. This process was validated by direct, histological, immunohistochemical examinations and also by evaluation of serum prostate-specific antigen (PSA) levels that decreased significantly already 7 hours posttreatment. In vitro studies of multicellular cell spheroids confirmed a PDT-induced decrease in ADC, suggesting that lipid peroxidation (LPO) significantly contributes to ADC decline observed after PDT. These results demonstrate that TOOKAD-based PDT successfully eradicates prostate adenocarcinoma xenografts and suggests DW-MRI to be useful for the detection of early tumor response and treatment outcome in the clinical setting.
