Matrix Metalloproteinases: Regulators of the Tumor Microenvironment

Metastasis causes most cancer deaths, yet this process remains one of the most enigmatic aspects of the disease. Building on new mechanistic insights emerging from recent research, we offer our perspective on the metastatic process and reflect on possible paths of future exploration. We suggest that metastasis can be portrayed as a two-phase process: The first phase involves the physical translocation of a cancer cell to a distant organ, whereas the second encompasses the ability of the cancer cell to develop into a metastatic lesion at that distant site. Although much remains to be learned about the second phase, we feel that an understanding of the first phase is now within sight, due in part to a better understanding of how cancer cell behavior can be modified by a cell-biological program called the epithelial-to-mesenchymal transition.

http://science.sciencemag.org/content/sci/331/6024/1559.full.pdf

A Perspective on Cancer Cell Metastasis

Cancer Metastasis: Building a Framework

https://www.cell.com/cell/pdf/S0092-8674(04)00576-8.pdf

Twist, a Master Regulator of Morphogenesis, Plays an Essential Role in Tumor Metastasis

Ever since Stephen Paget's 1889 hypothesis, metastatic organotropism has remained one of cancer's greatest mysteries. Here we demonstrate that exosomes from mouse and human lung-, liver- and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre-metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins α6β4 and α6β1 were associated with lung metastasis, while exosomal integrin αvβ5 was linked to liver metastasis. Targeting the integrins α6β4 and αvβ5 decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. Finally, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis.

/pdf/tumour-exosome-integrins-determine-organotropic-metastasis-379nlmfm16.pdf

Tumour exosome integrins determine organotropic metastasis

https://www.cell.com/cancer-cell/pdf/S1535-6108(03)00132-6.pdf

A multigenic program mediating breast cancer metastasis to bone.

Osteoblastic bone metastases are common in prostate and breast cancer patients, but mechanisms by which tumor cells stimulate new bone formation are unclear. We identified three breast cancer cell lines that cause osteoblastic metastases in a mouse model and secrete endothelin-1. Tumor-produced endothelin-1 stimulates new bone formation in vitro and osteoblastic metastases in vivo via the endothelin A receptor. Treatment with an orally active endothelin A receptor antagonist dramatically decreased bone metastases and tumor burden in mice inoculated with ZR-75-1 cells. Tumor-produced endothelin-1 may have a major role in the establishment of osteoblastic bone metastases, and endothelin A receptor blockade represents effective treatment.

https://www.pnas.org/content/pnas/100/19/10954.full.pdf

A causal role for endothelin-1 in the pathogenesis of osteoblastic bone metastases

Transforming Growth Factor-β Stimulates Parathyroid Hormone-related Protein and Osteolytic Metastases via Smad and Mitogen-activated Protein Kinase Signaling Pathways *

Sanna M. Kakonen

Papers

A multigenic program mediating breast cancer metastasis to bone.

A causal role for endothelin-1 in the pathogenesis of osteoblastic bone metastases

Transforming Growth Factor-β Stimulates Parathyroid Hormone-related Protein and Osteolytic Metastases via Smad and Mitogen-activated Protein Kinase Signaling Pathways *