Figure 7. Glycogen utilization fuels early metastasis.

(A) PAS Staining of human OvCa tissue Left, representative images of PAS staining indicating glycogen storage (deep purple stain) in early, microscopic omental implants (FIGO IIIA disease) and late, advanced metastasis (FIG IIIC) of high grade serous OvCa. Distase treatment (Tx) was used to specifically digest glycogen from the tissue prior to PAS staining. PAS positive, distase sensitive areas of tumor were quantified in early implants (n=11) and invasive tumor (n=12). Scale bar = 50μm. Right, the average percent PAS positive tumor area from 5 fields. Comparisons were made using an unpaired, one-way, Mann Whitney test, ***p< 0.001. (B) Glycogen content in early and late metastasis in colon, gastric, pancreatic, and serous endometrial cancer. Quantification of PAS staining comparing paired samples of early metastasis/micrometastases to large metastatic lesions (late metastasis) in the omentum from the same patient (n=7). Samples quantified as in Fig. 7A. Comparisons were made using a Wilcoxon matched-pairs signed rank test, **p< 0.01. (C) Model of CAF-mediated glycogen hydrolysis in cancer cells. OvCa cells store glycogen when excess glucose is available. During early metastasis, as the tumor takes hold, stromal changes occur, including the generation and recruitment of CAFs through TGF-β1. The tumor cells and CAFs then engage in bidirectional signaling: p38α MAPK is activated in CAFs resulting in CAF production of chemokines and cytokines that initiate the mobilization of glycogen stores in cancer cells through activation of glycogen phosphorylase. This burst of additional energy allows the cancer cells to begin high energy tasks such as migration, invasion and further metastasis.