Elevated collagen-I augments tumor progressive signals, intravasation and metastasis of prolactin-induced estrogen receptor alpha positive mammary tumor cells

Abstract

BackgroundThe development and progression of estrogen receptor alpha positive (ERα+) breast cancer has been linked epidemiologically to prolactin. However, activation of the canonical mediator of prolactin, STAT5, is associated with more differentiated cancers and better prognoses. We have reported that density/stiffness of the extracellular matrix potently modulates the repertoire of prolactin signals in human ERα + breast cancer cells in vitro: stiff matrices shift the balance from the Janus kinase (JAK)2/STAT5 cascade toward pro-tumor progressive extracellular regulated kinase (ERK)1/2 signals, driving invasion. However, the consequences for behavior of ERα + cancers in vivo are not known.MethodsIn order to investigate the importance of matrix density/stiffness in progression of ERα + cancers, we examined tumor development and progression following orthotopic transplantation of two clonal green fluorescent protein (GFP) + ERα + tumor cell lines derived from prolactin-induced tumors to 8-week-old wild-type FVB/N (WT) or collagen-dense (col1a1 tm1Jae/+) female mice. The latter express a mutant non-cleavable allele of collagen 1a1 “knocked-in” to the col1a1 gene locus, permitting COL1A1 accumulation. We evaluated the effect of the collagen environment on tumor progression by examining circulating tumor cells and lung metastases, activated signaling pathways by immunohistochemistry analysis and immunoblotting, and collagen structure by second harmonic generation microscopy.ResultsERα + primary tumors did not differ in growth rate, histologic type, ERα, or prolactin receptor (PRLR) expression between col1a1 tm1Jae/+ and WT recipients. However, the col1a1 tm1Jae/+ environment significantly increased circulating tumor cells and the number and size of lung metastases at end stage. Tumors in col1a1 tm1Jae/+ recipients displayed reduced STAT5 activation, and higher phosphorylation of ERK1/2 and AKT. Moreover, intratumoral collagen fibers in col1a1 tm1Jae/+ recipients were aligned with tumor projections into the adjacent fat pad, perpendicular to the bulk of the tumor, in contrast to the collagen fibers wrapped around the more uniformly expansive tumors in WT recipients.ConclusionsA collagen-dense extracellular matrix can potently interact with hormonal signals to drive metastasis of ERα + breast cancers.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-017-0801-1) contains supplementary material, which is available to authorized users.

Tumor Microenvironment Heterogeneity: Challenges and Opportunities

“…Several studies (Barcus et al, 2017; Beck et al, 2013; Iijima et al, 2011; Nguyen-Ngoc et al, 2012; Pickup et al, 2014; Wolf and Friedl) suggest that many ECM proteins play a major functional role in breast and prostate cancer progression and metastasis. Further, a number of the induced ECM proteins take part as essential components of metastatic niches and promote stem/progenitor signaling pathways and survival of cells within the metastatic niche.…”

Clinical significance and biological role of cancer‐derived Type I collagen in lung and esophageal cancers

“…Type I collagen either promotes or represses cell migration and positioning, depending on different contexts, such as cancer cell adhesion, proliferation, and differentiation . Type I collagen‐dense ECM can even drive the progression of estrogen receptor 1 (ERα + ) breast cancer by potentially altering hormonal signals . In addition, Type I collagen promotes embryonic stem cell growth, and contributes to the formation of solid cord‐like assemblies from microvascular endothelial cells after adopting an in vitro spindle‐shaped morphology …”

“…[5][6][7] Type I collagen-dense ECM can even drive the progression of estrogen receptor 1 (ERα + ) breast cancer by potentially altering hormonal signals. 8 In addition, Type I collagen promotes embryonic stem cell growth, 9 and contributes to the formation of solid cord-like assemblies from microvascular endothelial cells after adopting an in vitro spindleshaped morphology. 10 It is widely accepted that Type I collagen is produced by stromal fibroblasts.…”

Cancer-associated hypersialylated MUC1 drives the differentiation of monocytes into macrophages with a pathogenic phenotype

“…It is additionally interesting to note that 14/18 of the upregulated protein-validated factors are associated with poor prognosis or invasion in breast cancers, when measured in serum or tissue; this suggests that cells which secrete these factors would have a negative impact on prognosis 39,41,47,49,54,[56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72] . It is also of interest to note that in these studies 8/14 of these poorly prognostic factors have been seen to derive predominantly from stromal cells.…”