Metastatic Outgrowth Encompasses COL-I, FN1, and POSTN Up-Regulation and Assembly to Fibrillar Networks Regulating Cell Adhesion, Migration, and Growth

Abstract

Although the outgrowth of micrometastases into macrometastases is the rate-limiting step in metastatic progression and the main determinant of cancer fatality, the molecular mechanisms involved have been little studied. Here, we compared the gene expression profiles of melanoma lymph node micro- and macrometastases and unexpectedly found no common up-regulation of any single growth factor/cytokine, except for the cytokine-like SPP1. Importantly, metastatic outgrowth was found to be consistently associated with activation of the transforming growth factor-beta signaling pathway (confirmed by phospho-SMAD2 staining) and concerted up-regulation of POSTN, FN1, COL-I, and VCAN genes-all inducible by transforming growth factor-beta. The encoded extracellular matrix proteins were found to together form intricate fibrillar networks around tumor cell nests in melanoma and breast cancer metastases from various organs. Functional analyses suggested that these newly synthesized protein networks regulate adhesion, migration, and growth of tumor cells, fibroblasts, and endothelial cells. POSTN acted as an anti-adhesive molecule counteracting the adhesive functions of FN1 and COL-I. Further, cellular FN and POSTN were specifically overexpressed in the newly forming/formed tumor blood vessels. Transforming growth factor-beta receptors and the metastasis-related matrix proteins, POSTN and FN1, in particular, may thus provide attractive targets for development of new therapies against disseminated melanoma, breast cancer, and possibly other tumors, by affecting key processes of metastasis: tumor/stromal cell migration, growth, and angiogenesis.

Matrix architecture defines the preferential localization and migration of T cells into the stroma of human lung tumors

“…It has previously been suggested that a tumor may be perceived by the organism as a permanent wound, with tissue damage triggering a healing process that may in turn favor tumor growth and metastasis (23). The structural feature we described here in lung tumors - dense parallel fibers adjacent to tumor islets - has also been observed in human melanoma and breast cancer metastases (24). In a mouse breast tumor model, collagen strands adjacent to tumor nests adopt several patterns during carcinoma progression, including similar ring structures around tumor cell regions that were observed at early stages of tumorigenesis (25).…”

The non-coding 3' UTR of CD44 induces metastasis by regulating extracellular matrix functions

“…Furthermore, high levels of type 1 collagen have also been found in metastatic lesions (Brown et al, 1999;Jensen et al, 2002). Recently, Soikkeli and co-workers reported that both FN1 and Col1a1 are involved in promoting cell migration, invasion and metastasis due to their increased expression and interaction with other matrix network proteins (Soikkeli et al, 2010). However, similar to reports on the dual nature of CD44, there have also been reports of a decreased synthesis of collagen by cells in culture upon oncogenic transformation through treatment with viruses or chemical carcinogens (Adams et al, 1977;Smith and Niles, 1980).…”

Breast cancer lung metastasis: Molecular biology and therapeutic implications

“…126 TNC, normally produced by fibroblasts, can also be expressed by BCSCs. 127 This aberrant expression of TNC by BCSCs exerts a metastasis-initiating effect for niche formation for lung colonization.…”