Suppression and Activation of the Malignant Phenotype by Extracellular Matrix in Xenograft Models of Bladder Cancer: A Model for Tumor Cell “Dormancy”

Abstract

A major problem in cancer research is the lack of a tractable model for delayed metastasis. Herein we show that cancer cells suppressed by SISgel, a gel-forming normal ECM material derived from Small Intestine Submucosa (SIS), in flank xenografts show properties of suppression and re-activation that are very similar to normal delayed metastasis and suggest these suppressed cells can serve as a novel model for developing therapeutics to target micrometastases or suppressed cancer cells. Co-injection with SISgel suppressed the malignant phenotype of highly invasive J82 bladder cancer cells and highly metastatic JB-V bladder cancer cells in nude mouse flank xenografts. Cells could remain viable up to 120 days without forming tumors and appeared much more highly differentiated and less atypical than tumors from cells co-injected with Matrigel. In 40% of SISgel xenografts, growth resumed in the malignant phenotype after a period of suppression or dormancy for at least 30 days and was more likely with implantation of 3 million or more cells. Ordinary Type I collagen did not suppress malignant growth, and tumors developed about as well with collagen as with Matrigel. A clear signal in gene expression over different cell lines was not seen by transcriptome microarray analysis, but in contrast, Reverse Phase Protein Analysis of 250 proteins across 4 cell lines identified Integrin Linked Kinase (ILK) signaling that was functionally confirmed by an ILK inhibitor. We suggest that cancer cells suppressed on SISgel could serve as a model for dormancy and re-awakening to allow for the identification of therapeutic targets for treating micrometastases.

Synergistic anti-tumor effects of combined gemcitabine and cisplatin nanoparticles in a stroma-rich bladder carcinoma model

“…Fibroblasts were subcutaneously co-injected along with cancerous cells and Matrigel, a permissive extracellular matrix preparation. When grown on Matrigel in vivo , bladder carcinoma cells adopt a more characteristic phenotype [15] and the xenograft better resembles the original tumor when compared to the more commonly used model.…”

Discoidin Domain Receptors, DDR1b and DDR2, Promote Tumour Growth within Collagen but DDR1b Suppresses Experimental Lung Metastasis in HT1080 Xenografts

“…This notion was established, in part, in multiple studies with xenograft models of cancer in which the composition and biophysical properties of the collagenous matrix were altered by modulating the synthesis, cross-linking, cleavage, and stiffness of collagen [119][120][121][122][123][124][125][126][127] . Also, a number of studies utilized collagen I gels to inoculate tumour cells in vivo [81][82][83][84] , demonstrating a tumour-promoting effect of collagen. Yet, evidence indicate that collagen matrices can elicit divergent effects on tumour cells by either promoting or suppressing malignant activity 128 .…”

“…COL1 has no impact on HT1080 tumour growth in the absence of recombinant DDR induction. Because COL1 matrices can positively influence tumour growth in vivo [81][82][83][84] , we further examined any potential effects of COL1 on s.c. HT1080 tumour growth independent of DDR induction. To this end, we compared the growth rate of HT-DDR1b and HT-DDR2 cells co-implanted with or without COL1 in mice fed a +DOX diet (DDR repression).…”

Identification of novel drugs to target dormant micrometastases

“…Compounds were diluted to 100 μM before use. SISgel was prepared as described previously [ 33 , 34 ] from powdered porcine small intestine submucosa obtained from Cook Biotech (W. Lafayette, IN). It is a natural product that is used extensively in tissue engineering as a bioscaffold [ 34 ].…”