Intra-abdominal tumors, such as ovarian cancer1,2, have a clear predilection for metastasis to the omentum, an organ primarily composed of adipocytes. Currently, it is unclear why tumor cells preferentially home to and proliferate in the omentum, yet omental metastases typically represent the largest tumor in the abdominal cavities of women with ovarian cancer. We show here that primary human omental adipocytes promote homing, migration and invasion of ovarian cancer cells, and that adipokines including interleukin-8 (IL-8) mediate these activities. Adipocyte–ovarian cancer cell coculture led to the direct transfer of lipids from adipocytes to ovarian cancer cells and promoted in vitro and in vivo tumor growth. Furthermore, coculture induced lipolysis in adipocytes and β-oxidation in cancer cells, suggesting adipocytes act as an energy source for the cancer cells. A protein array identified upregulation of fatty acid–binding protein 4 (FABP4, also known as aP2) in omental metastases as compared to primary ovarian tumors, and FABP4 expression was detected in ovarian cancer cells at the adipocyte-tumor cell interface. FABP4 deficiency substantially impaired metastatic tumor growth in mice, indicating that FABP4 has a key role in ovarian cancer metastasis. These data indicate adipocytes provide fatty acids for rapid tumor growth, identifying lipid metabolism and transport as new targets for the treatment of cancers where adipocytes are a major component of the microenvironment.

Ovarian cancer (OvCa) is characterized by widespread and rapid metastasis in the peritoneal cavity. Visceral adipocytes promote this process by providing fatty acids (FAs) for tumour growth. However, the exact mechanism of FA transfer from adipocytes to cancer cells remains unknown. This study shows that OvCa cells co-cultured with primary human omental adipocytes express high levels of the FA receptor, CD36, in the plasma membrane, thereby facilitating exogenous FA uptake. Depriving OvCa cells of adipocyte-derived FAs using CD36 inhibitors and short hairpin RNA knockdown prevented development of the adipocyte-induced malignant phenotype. Specifically, inhibition of CD36 attenuated adipocyte-induced cholesterol and lipid droplet accumulation and reduced intracellular reactive oxygen species (ROS) content. Metabolic analysis suggested that CD36 plays an essential role in the bioenergetic adaptation of OvCa cells in the adipocyte-rich microenvironment and governs their metabolic plasticity. Furthermore, the absence of CD36 affected cellular processes that play a causal role in peritoneal dissemination, including adhesion, invasion, migration and anchorage independent growth. Intraperitoneal injection of CD36-deficient cells or treatment with an anti-CD36 monoclonal antibody reduced tumour burden in mouse xenografts. Moreover, a matched cohort of primary and metastatic human ovarian tumours showed upregulation of CD36 in the metastatic tissues, a finding confirmed in three public gene expression datasets. These results suggest that omental adipocytes reprogram tumour metabolism through the upregulation of CD36 in ovarian cancer cells. Targeting the stromal-tumour metabolic interface via CD36 inhibition may prove to be an effective treatment strategy against OvCa metastasis.

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Although a reliable method for detection of cancer cells in blood would be an important tool for diagnosis and monitoring of solid tumors in early stages, current technologies cannot reliably detect the extremely low concentrations of these rare cells. The preferred method of detection, automated digital microscopy (ADM), is too slow to scan the large substrate areas. Here we report an approach that uses fiber-optic array scanning technology (FAST), which applies laser-printing techniques to the rare-cell detection problem. With FAST cytometry, laser-printing optics are used to excite 300,000 cells per sec, and emission is collected in an extremely wide field of view, enabling a 500-fold speed-up over ADM with comparable sensitivity and superior specificity. The combination of FAST enrichment and ADM imaging has the performance required for reliable detection of early-stage cancer in blood.O ccult tumor cells (OTCs) shed from tumors can travel through the blood stream to anatomically distant sites and form metastatic disease, the major cause of cancer-related death in patients with solid tumors. These disseminated cells are present in circulation in extremely low concentrations, estimated to be in the range of one tumor cell in the background of 10 6 -10 7 normal blood cells and are occult to routine imaging and laboratory studies (1). Automated digital microscopy (ADM) using image analysis for recognition of specifically labeled tumor cells has been demonstrated to be the most reliable method currently available for OTC detection (2-5).However, at the typical scan rate of 800 cells per sec, ADM is too slow to screen for a statistically valid number of OTCs (6). This slow scan rate is a result of two factors. One is the substantial latency associated with stepping the sample under the microscopy objective. This stepping results from the lens' small field of view. The other factor is the long exposure time that is due to the low level of excitation from broadband illumination sources and the lack of sensitivity of the charge-coupled device detector used for imaging.Here we report a scanning instrument using fiber-optic array scanning technology (FAST) that can locate OTCs at a rate that is 500 times faster than ADM, with comparable sensitivity and improved specificity. The exposure time is reduced by using a laser source for higher illumination levels and a more sensitive photomultiplier detector. However, our key innovation is providing an optical system with an exceptionally large field of view (50 mm) without a loss of collection efficiency. By collecting the fluorescence in an array of optical fibers that forms a wide collection aperture, the FAST cytometer has a 100-fold increase in field of view over ADM. Although this increase in field of view comes with a reduction in instrument resolution, the resolution is still sufficient for the identification of fluorescently labeled cells. This field of view is large enough to eliminate the need to step the sample under the collection optics, and hence there is no s...