title: Lymph node stromal cells enhance drug-resistant colon cancer cell tumor formation through SDF-1α/CXCR4 paracrine signaling.
abstract: Colorectal cancer (CRC) is the third most common malignancy and the second leading cause of cancer-related deaths in America. Nearly two thirds of newly diagnosed CRC cases include lymph node (LN) involvement, and LN metastasis is one of the strongest negative prognostic factors for CRC. It is thought that CRC tumors contain a small population of drug-resistant CRC tumor-initiating cells (Co-TICs) that may be responsible for cancer recurrence. To evaluate the effects of the LN stromal cells on Co-TICs, we established a unique xenoplant model using CRC cells isolated by enzymatic digestion from consented patient specimens, HT-29 cells, HCA-7 cells, and LN stromal cell line HK cells. We found that HK cells and HK cell-conditioned media enhanced CRC tumor formation and tumor angiogenesis. Cells expressing CD133(+) and the stromal cell-derived factor 1α (SDF-1α) receptor CXCR4 were enriched in chemotherapeutic-resistant CRC cells. CD133(+)CXCR4(+) Co-TICs isolated from patient specimens are more tumorigenic than unsorted tumor cells. Furthermore, the inhibitors specific to HK cell-derived SDF-1α reduced tumor formation and tumor angiogenesis. Our results have demonstrated a role for Co-TICs in tumor growth and defined the influence of LN stromal cells on Co-TICs. We have identified a major Co-TIC/LN microenvironment-specific mechanism for CRC resistance to chemotherapeutic agents and established experimental platforms for both in vitro and in vivo testing, indicating that SDF-1α and its receptor, CXCR4, may be targets for clinical therapy.
authors.affiliation: Department of Colon Rectal Surgery, Ochsner Clinic Foundation, New Orleans, LA, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Margolin
authors.forename: Jennifer
authors.initials: J
authors.lastname: Silinsky
authors.forename: Chelsea
authors.initials: C
authors.lastname: Grimes
authors.forename: Nakia
authors.initials: N
authors.lastname: Spencer
authors.forename: Melissa
authors.initials: M
authors.lastname: Aycock
authors.forename: Heather
authors.initials: H
authors.lastname: Green
authors.forename: Jose
authors.initials: J
authors.lastname: Cordova
authors.forename: Nancy K
authors.initials: NK
authors.lastname: Davis
authors.forename: Tiffany
authors.initials: T
authors.lastname: Driscoll
authors.forename: Li
authors.initials: L
authors.lastname: Li
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D054377:Chemokine CXCL12 / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D006023:Glycoproteins / Q000096:biosynthesis*; D006801:Humans; D008198:Lymph Nodes / Q000166:cytology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D019899:Paracrine Communication; D010455:Peptides; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015398:Signal Transduction; D017154:Stromal Cells / Q000502:physiology*; D014183:Transplantation, Heterologous
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D019718:Receptors, CXCR4