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Comparative Study
. 2007 Aug;117(8):2114-22.
doi: 10.1172/JCI31334.

Overexpression of PDGF-BB decreases colorectal and pancreatic cancer growth by increasing tumor pericyte content

Marya F McCarty  1 , Ray J Somcio, Oliver Stoeltzing, Jane Wey, Fan Fan, Wenbiao Liu, Corazon Bucana, Lee M Ellis
Affiliations
Comparative Study

Overexpression of PDGF-BB decreases colorectal and pancreatic cancer growth by increasing tumor pericyte content

Marya F McCarty et al. J Clin Invest. 2007 Aug.

Abstract

We hypothesized that overexpression of PDGF-BB in colorectal cancer (CRC) and pancreatic cancer cells would result in increased pericyte coverage of ECs in vivo, rendering the tumor vasculature more resistant to antiangiogenic therapy. We stably transfected the cDNA for the PDGF-B into HT-29 human CRC and FG human pancreatic cancer cells. Surprisingly, when HT-29 or FG parental and transfected cells were injected into mice (subcutaneously and orthotopically), we observed marked inhibition of tumor growth in the PDGF-BB-overexpressing clones. In the PDGF-BB-overexpressing tumors, we observed an increase in pericyte coverage of ECs. Treatment of PDGF-BB-overexpressing tumors with imatinib mesylate (PDGFR inhibitor) resulted in increased growth and decreased total pericyte content compared with those in untreated PDGF-BB-overexpressing tumors. In vitro studies demonstrated the ability of VSMCs to inhibit EC proliferation by approximately 50%. These data show that increasing the pericyte content of the tumor microenvironment inhibits the growth of angiogenesis-dependent tumors. Single-agent therapy targeting PDGF receptor must be used with caution in tumors when PDGFR is not the target on the tumor cell itself.

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Figures

Figure 1
Figure 1. Effect of PDGF-BB overexpression on growth of subcutaneous tumors.
Human colon cancer cell lines HT-29 (parental), HT-29 Neo pool, HT-29 S2 (PDGF-BB–overexpressing), and HT-29 S4 (PDGF-BB–overexpressing) (1 × 106) were injected subcutaneously into nude mice. (A) Tumor growth was measured 3 times weekly (Monday, Wednesday, and Friday) until tumors became necrotic or larger than 1 cm3. (B) Photomicrographs of representative tumors from each group. HT-29 S2 and HT-29 S4 cells demonstrated decreased tumor growth and a significant reduction in end-stage tumor mass in vivo. *P < 0.05. Original magnification, ×1.
Figure 2
Figure 2. Effect of PDGF-BB overexpression on pericyte coverage.
HT-29 tumor sections from mice injected with HT-29 control (Neo pool) or PDGF-BB–overexpressing (S2) cells were double stained for ECs (CD31; red) and pericyte markers (NG2 and α-SMA; green). There was an increased influx of pericytes or pericyte-like cells within the PDGF-BB–overexpressing tumors. Representative photomicrographs are shown for the HT-29 Neo pool and the HT-29 S2 groups. Scale bar: 50 μm.
Figure 3
Figure 3. Effect of PDGF-BB overexpression on tumor growth in the liver.
HT-29 control (Neo pool), and PDGF-BB–overexpressing (S2 and S4) cells (1 × 106) were injected directly into the livers of nude mice. Mice were sacrificed, and the tumors were measured and weighed. There was a significant reduction in tumor mass in the PDGF-BB–overexpressing tumors. *P < 0.001. Original magnification, ×1.
Figure 4
Figure 4. Effect of PDGF-BB overexpression in HT-29 cells on VSMCs.
(A) Conditioned medium from HT-29 parental, control (Neo pool), and PDGF-BB–overexpressing (S2 and S4) cell lines was plated onto VSMCs for 72 hours. MTT analysis was then performed. There was increased proliferation of VSMCs in response to conditioned medium from PDGF-BB–overexpressing HT-29 cells relative to controls. (B) Tumor cells were then plated in the bottom of a modified Boyden chamber and allowed to adhere overnight. VSMCs were plated on top and were allowed to migrate for 24 hours in response to the tumor cells. We observed an increase in VSMC migration in response to the PDGF-BB–overexpressing HT-29 cells relative to controls. HPF, high-power field. *P < 0.05.
Figure 5
Figure 5. Inhibition of EC proliferation in vitro in the presence of pericytes.
HUVECs and 10T 1/2 cells were labeled with fluorescent red or green dye. HUVECs were then plated onto a 6-well plate with either undyed HUVECs or 10T 1/2 cells. After 48 hours of coculture, cells were trypsinized, and HUVECs were sorted using FACS analysis. The total number of fluorescent red cells (HUVECs) was determined as a percentage of the control. 10T 1/2 cells inhibited HUVEC growth by almost 50% compared with cells that were in culture with unstained HUVECs. *P < 0.05.
Figure 6
Figure 6. Effect of imatinib mesylate on tumor growth in vivo.
HT-29 Neo pool and HT-29 S2 cells (1 × 106) were injected subcutaneously into nude mice. Imatinib mesylate was administered daily by oral gavage beginning on day 7. Treatment of PDGF-BB–overexpressing cells with imatinib mesylate increased tumor growth. (A) Volume. (B) Mass. *P < 0.05.
Figure 7
Figure 7. Effect of imatinib mesylate on pericyte coverage of HT-29 tumors.
HT-29 tumors were double-stained for ECs and pericyte markers. NG2 staining (red) was used as a marker of pericytes or pericyte-like cells, whereas CD31 (blue) was used to identify ECs. There was an increased influx of NG2-positive cells within the PDGF-BB–overexpressing tumors, similar to what was shown previously (Figure 2). This influx was reduced in the imatinib mesylate–treated group, in which pericyte coverage appeared similar to that in control tumors. Representative photomicrographs are shown for each group. Scale bar: 50 μm.
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References

    1. Ellis L.M. A targeted approach for antiangiogenic therapy of metastatic human colon cancer. Am. Surg. 2003;69:3–10. - PubMed
    1. Jung Y.D., et al. The role of the microenvironment and intercellular cross-talk in tumor angiogenesis. Semin. Cancer Biol. 2002;12:105–112. - PubMed
    1. von Tell D., Armulik A., Betsholtz C. Pericytes and vascular stability. Exp. Cell Res. 2006;312:623–629. - PubMed
    1. Gerhardt H., Betsholtz C. Endothelial-pericyte interactions in angiogenesis. Cell Tissue Res. 2003;314:15–23. - PubMed
    1. Sims D.E. Diversity within pericytes. Clin. Exp. Pharmacol. Physiol. 2000;27:842–846. - PubMed

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