Macrophage Sensors for Early Cancer Detection.
Macrophage Sensors for Early Cancer Detection.
复制标题
用于早期癌症检测的巨噬细胞传感器。
DOI：
10.1093/clinchem/hvz017
复制
发表时间：
2020
影响因子：
9.3
通讯作者：
Kwong,GabrielA
中科院分区：
文献类型：
--
作者：
Kwong,GabrielA
Along the patient continuum of care, the ability to detect cancer at an early stage has an enormous impact on successful drug treatment and patient outcomes. For example, in ovarian cancer, 5-year survival rates rise sharply from 20% to greater than 90% when lesions are detected at stage I rather than IV, yet only 15% of patients are detected at the earliest stage due to the poor diagnostic sensitivity of screening. The challenges that limit tumor-shed, or endogenous, biomarkers for early detection are multifaceted. Biomarkers shed from nascent disease sites—which are on the order of a few cubic millimeters in volume but already contain millions of tumor cells—can be diluted by up to 100 000-fold in circulation, making them extremely challenging to detect even with ultrasensitive analytical platforms. Moreover, endogenous biomarkers are secreted by tumor cells at low rates (or not at all) and once in the blood stream biomarkers are rapidly cleared from circulation or are degraded. For biomarkers such as cell-free RNA, their circulation half-lives in blood can be as low as several minutes. Estimates using multicompartment mass transport models have shown that tumor-shed blood biomarkers are at such low concentrations that early tumors may remain undetectable for an entire decade following tumorigenesis (1, 2) based on the detection limits of current biomedical diagnostics. Thus, there remains a stark mismatch between the smallest tumors that can be indicated by blood biomarkers (> 2–5 cm) and the size of early stage tumors that would best respond to treatment (< 1–5 mm). The early cancer detection problem is motivating the development of a new class of diagnostics called synthetic biomarkers. The premise is based on the recognition that tumor-shed biomarkers are ultimately limited in diagnostic sensitivity by fundamental mass transport challenges that pose substantial barriers for improvement. Therefore, instead of relying on nature’s biomarkers, the route to early cancer detection may require new approaches that focus on synthetic agents that are precisely engineered to sense, target, and amplify early cancer detection signals in vivo. Recent work has shown that this approach has promise. Systemic delivery of DNA “minicircles” that contain a tumor-specific promoter to drive expression of an exogenous biomarker has been shown to be selectively activated by malignant cells (3), thereby revealing the presence of tumors in mice. By targeting dysregulated protease activity in early tumors, activity-based probes were shown to amplify early cancer detection signals into host urine, providing the ability to discriminate tumors in mice with high diagnostic sensitivity and specificity compared to FDA-approved blood biomarkers (4). In a recent issue of Nature Biotechnology, Gambhir and co-authors report the concept of cell-based “immunodiagnostics” by exploiting M2 polarization of macrophages within the tumor microenvironment (TME) as a selective trigger to release a secreted biomarker in adoptively transferred macrophages (5) as a cell-based diagnostic. Without TME cues, these engineered macrophages do not polarize, thereby ensuring detection signals are tumor-specific (Fig. 1).The authors selected macrophages as a pan-cancer diagnostic cell-sensor based on its high prevalence across different types of cancers. In tumors, macrophages adopt a tumor-associated M2 polarization state that is involved in promoting an immunosuppressive TME. The authors first tested macrophage (both bone-marrow-derived macrophages and RAW264. 7) response to immunosuppressive cytokines and tumor-conditioned media, and found a significant …
