RESUMO
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and treatment-refractory malignancies. The lack of an effective screening tool results in the majority of patients being diagnosed at late stages, which underscores the urgent need to develop more sensitive and specific imaging modalities, particularly in detecting occult metastases, to aid clinical decision-making. The tumor microenvironment of PDAC is heavily infiltrated with myeloid-derived suppressor cells (MDSCs) that express C-C chemokine receptor type 2 (CCR2). These CCR2-expressing MDSCs accumulate at a very early stage of metastasis and greatly outnumber PDAC cells, making CCR2 a promising target for detecting early, small metastatic lesions that have scant PDAC cells. Herein, we evaluated a CCR2 targeting PET tracer (68Ga-DOTA-ECL1i) for PET imaging on PDAC metastasis in two mouse models. Positron emission tomography/computed tomography (PET/CT) imaging of 68Ga-DOTA-ECL1i was performed in a hemisplenic injection metastasis model (KI) and a genetically engineered orthotopic PDAC model (KPC), which were compared with 18F-FDG PET concurrently. Autoradiography, hematoxylin and eosin (H&E), and CCR2 immunohistochemical staining were performed to characterize the metastatic lesions. PET/CT images visualized the PDAC metastases in the liver/lung of KI mice and in the liver of KPC mice. Quantitative uptake analysis revealed increased metastasis uptake during disease progression in both models. In comparison, 18F-FDG PET failed to detect any metastases during the time course studies. H&E staining showed metastases in the liver and lung of KI mice, within which immunostaining clearly demonstrated the overexpression of CCR2 as well as CCR2+ cell infiltration into the normal liver. H&E staining, CCR2 staining, and autoradiography also confirmed the expression of CCR2 and the uptake of 68Ga-DOTA-ECL1i in the metastatic foci in KPC mice. Using our novel CCR2 targeted radiotracer 68Ga-DOTA-ECL1i and PET/CT, we demonstrated the sensitive and specific detection of CCR2 in the early PDAC metastases in two mouse models, indicating its potential in future clinical translation.
RESUMO
CD36 mediates the uptake of long-chain fatty acids (FAs), a major energy substrate for the myocardium. Under excessive FA supply, CD36 can cause cardiac lipid accumulation and inflammation while its deletion reduces heart FA uptake and lipid content and increases glucose utilization. As a result, CD36 was proposed as a therapeutic target for obesity-associated heart disease. However, more recent reports have shown that CD36 deficiency suppresses myocardial flexibility in fuel preference between glucose and FAs, impairing tissue energy balance, while CD36 absence in tissue macrophages reduces efferocytosis and myocardial repair after injury. In line with the latter homeostatic functions, we had previously reported that CD36-/- mice have chronic subclinical inflammation. Lipids are important for the maintenance of tissue homeostasis and there is limited information on heart lipid metabolism in CD36 deficiency. Here, we document in the hearts of unchallenged CD36-/- mice abnormalities in the metabolism of triglycerides, plasmalogens, cardiolipins, acylcarnitines, and arachidonic acid, and the altered remodeling of these lipids in response to an overnight fast. The hearts were examined for evidence of inflammation by monitoring the presence of neutrophils and pro-inflammatory monocytes/macrophages using the respective positron emission tomography (PET) tracers, 64Cu-AMD3100 and 68Ga-DOTA-ECL1i. We detected significant immune cell infiltration in unchallenged CD36-/- hearts as compared with controls and immune infiltration was also observed in hearts of mice with cardiomyocyte-specific CD36 deficiency. Together, the data show that the CD36-/- heart is in a non-homeostatic state that could compromise its stress response. Non-invasive immune cell monitoring in humans with partial or total CD36 deficiency could help evaluate the risk of impaired heart remodeling and disease.