The Tyrosine Kinase Inhibitor Imatinib Augments Extracellular Fluid Exchange and Reduces Average Collagen Fibril Diameter in Experimental Carcinoma

Abstract

A typical obstacle to cancer therapy is the limited distribution of low molecular weight anticancer drugs within the carcinoma tissue. In experimental carcinoma, imatinib (STI571) increases efficacy of synchronized chemotherapy, reduces tumor interstitial fluid pressure, and increases interstitial fluid volume. STI571 also increases the water-perfusable fraction in metastases from human colorectal adenocarcinomas. Because the mechanism(s) behind these effects have not been fully elucidated, we investigated the hypothesis that STI571 alters specific properties of the stromal extracellular matrix. We analyzed STI571-treated human colorectal KAT-4/HT-29 experimental carcinomas, known to have a welldeveloped stromal compartment, for solute exchange and glycosaminoglycan content, as well as collagen content, structure, and synthesis. MRI of STI571-treated KAT-4/HT-29 experimental carcinomas showed a significantly increased efficacy in dynamic exchanges of solutes between tumor interstitium and blood. This effect was paralleled by a distinct change of the stromal collagen network architecture, manifested by a decreased average collagen fibril diameter, and increased collagen turnover. The glycosaminoglycan content was unchanged. Furthermore, the apparent effects on the stromal cellular composition were limited to a reduction in an NG2-positive stromal cell population. The current data support the hypothesis that the collagen network architecture influences the dynamic exchanges of solutes between blood and carcinoma tissue. It is conceivable that STI571 reprograms distinct nonvascular stromal cells to produce a looser extracellular matrix, ultimately improving transport characteristics for traditional chemotherapeutic agents. Mol Cancer Ther; 15(10); 2455-64. Ó2016 AACR.

The role of collagen in cancer: from bench to bedside

“…Interfering collagen biosynthesis enzymes Collagen genes MiR-129-5p, MiR-29b, MiR-384 [275][276][277] Prolyl 4-hydroxylase Budesonide, catechol, N-oxalylglycine, coumalic acid, ethyl dihydroxybenzoic acid [278][279][280] Heat shock protein 90 1G6-D7, dipalmitoyl-radicicol, 17-DMAG, ganetespib [281][282][283][284] Heat shock protein 47 MiR-29, 1,3-dimethylol-5-FU, AK778, pirfenidone, terutroban [285,286] Matrix metalloproteinases Gallium complex GS2, isoflavonoids, bisphosphonates [287,288] Lysyl oxidases Beta-aminopropionitrile [289] Disturbing cancer cell signaling pathways Snail transcription factors Toosendanin, ponicidin, ferulic acid [290] Hypoxia-inducible factor Tamoxifen, 28-O-propynoylbetulin [291,292] STAT3 signaling pathway VS-4718, stattic, ruxolitinib, S3I-201 [293,294] TGF-β signaling pathway LY2157299 monohydrate, trabedersen, fresolimumab, galunisertib [295,296] NF-κB signaling pathway Honokiol, aspirin, ormeloxifene [297][298][299] AKT signaling pathway Quetiapine, pirfenidone [300] Notch signaling pathway Rovalpituzumab tesirine, taladegib, crenigacestat, MiR-148a [301] Hedgehog signaling pathway Itraconazole, sonidegib, vismodegib [302] RAS signaling pathway Perindopril, losartan [100,303] Tyrosine kinase receptor Bevacizumab, imatinib, ponatinib, dasatinib [304,305] Discoidin domain receptor WRG-28, 7rh, AZD0156 [306][307][308] G protein family receptor AT13148, KD025, Azaindole 1, chelerythrine…”

The endoplasmic reticulum–resident collagen chaperone Hsp47 interacts with and promotes the secretion of decorin, fibromodulin, and lumican

“…Here, we wanted to explore whether small leucine-rich proteins (SLRPs) are involved in early collagen biosynthesis in the ER via complex formation with other intracellular collagenassociated proteins. SLRPs are already known to modulate the phenotype of collagen fibrils and their cross-linking in the extracellular space (25)(26)(27)(28); thus, we hypothesized that their function might be required at the rER or ER exit sites for and during secretion of procollagen. Such a, yet unknown, mechanism would ensure a proper modulatory SLRP function during the early, intracellular stages of collagen fibrillogenesis (i.e.…”

Fibromodulin deficiency reduces collagen structural network but not glycosaminoglycan content in a syngeneic model of colon carcinoma

“…Human colon adenocarcinoma KAT-4/HT-29 (American Type Culture Collection, LGC Standards GmbH, Wesel Germany) were initially described as originating from a thyroid tumor [ 27 ]; however, a thyroid origin of the KAT-4 carcinoma was later questioned and the cells have been identified as originating from colorectal adenocarcinoma cell line HT-29 [ 12 , 28 ].…”

“…Furthermore, expression of fibromodulin decreases in experimental carcinomas treated with a specific inhibitor of TGF-ß1 and -ß3, which correlates with decreased collagen fibril thickness [ 22 ]. Similarly, treatment of experimental carcinoma with Imatinib reduces collagen fibril thickness [ 12 ].…”