Overexpression of PDGF-BB decreases colorectal and pancreatic cancer growth by increasing tumor pericyte content.
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.
McCarty
Marya F
MF
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77230-1402, USA.
Somcio
Ray J
RJ
Stoeltzing
Oliver
O
Wey
Jane
J
Fan
Fan
F
Liu
Wenbiao
W
Bucana
Corazon
C
Ellis
Lee M
LM
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D000077214:Becaplermin; D001549:Benzamides; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018076:DNA, Complementary; D015870:Gene Expression; D006801:Humans; D000068877:Imatinib Mesylate; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020286:Pericytes / Q000378:metabolism* / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D010982:Platelet-Derived Growth Factor / Q000096:biosynthesis* / Q000235:genetics; D020574:Proto-Oncogene Proteins c-sis; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D014162:Transfection
D000970:Antineoplastic Agents; D001549:Benzamides; D018076:DNA, Complementary; D010879:Piperazines; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D011743:Pyrimidines; D000077214:Becaplermin; D000068877:Imatinib Mesylate; D017479:Receptors, Platelet-Derived Growth Factor