LOX-Mediated Collagen Crosslinking Is Responsible for Fibrosis-Enhanced Metastasis

Abstract

Tumor metastasis is a highly complex, dynamic, and inefficient process involving multiple steps, yet it accounts for more than 90% of cancer-related deaths. Although it has long been known that fibrotic signals enhance tumor progression and metastasis, the underlying molecular mechanisms are still unclear. Identifying events involved in creating environments that promote metastatic colonization and growth are critical for the development of effective cancer therapies. Here, we show a critical role for lysyl oxidase (LOX) in establishing a milieu within fibrosing tissues that is favorable to growth of metastastic tumor cells. We show that LOX-dependent collagen crosslinking is involved in creating a growth-permissive fibrotic microenvironment capable of supporting metastatic growth by enhancing tumor cell persistence and survival. We show that therapeutic targeting of LOX abrogates not only the extent to which fibrosis manifests, but also prevents fibrosis-enhanced metastatic colonization. Finally, we show that the LOXmediated collagen crosslinking directly increases tumor cell proliferation, enhancing metastatic colonization and growth manifesting in vivo as increased metastasis. This is the first time that crosslinking of collagen I has been shown to enhance metastatic growth. These findings provide an important link between ECM homeostasis, fibrosis, and cancer with important clinical implications for both the treatment of fibrotic disease and cancer. Cancer Res; 73(6);

Fibrosis, Cancer and the Premetastatic Niche

“…To that end, it has been proposed that the treatment of underlying fibrosis in such cases would lead to an improvement in cancer associated prognosis [13]. In our work last year, we showed that tissue fibrosis may pose a serious clinical problem in patients harboring unrelated primary tumors [6]. The presence of pathological organ fibrosis in both the lung and the liver increases the ability of circulating breast cancer cells to colonize and grow in these organs, suggesting that breast cancer patients with unrelated organ fibrosis may present a poorer metastasis-free survival.…”

“…Early on in tumorigenesis, this homeostasis is upset and the ECM begins to change in both its biochemical as well as its biomechanical properties. In the case of breast cancer, it has been shown that these desmoplastic changes, driven primarily by collagen I accumulation, are a key component of the tumor microenvironment [1] and act to drive malignant transformation [2], but also drive tumor progression [3,4] and ultimately metastasis [5,6]. Yet this disruption to homeostatic ECM mechanisms is not confined to the primary tumor site.…”

“…A key family shown to play a pivotal role in these two diseases in the lysyl oxidase (LOX) family of proteins, in particular LOX and LOX-like 2 (LOXL-2) [16,17]. Both of these proteins have been shown to be important in ECM remodeling and homeostasis, and to play critical roles in both breast cancer and fibrosis [6,7,[18][19][20] driving the accumulation of collagen fibers. Indeed, a role for LOX and LOXL-2 has been shown in chronic hepatic fibrosis, arterial fibrosis and chemotherapy-induced kidney fibrosis in human patients [21], as well as liver and lung fibrosis in mouse models [6,18].…”

“…Both of these proteins have been shown to be important in ECM remodeling and homeostasis, and to play critical roles in both breast cancer and fibrosis [6,7,[18][19][20] driving the accumulation of collagen fibers. Indeed, a role for LOX and LOXL-2 has been shown in chronic hepatic fibrosis, arterial fibrosis and chemotherapy-induced kidney fibrosis in human patients [21], as well as liver and lung fibrosis in mouse models [6,18]. While targeting fibrosis has proved problematic in the past, several therapeutic approaches are being explored and clinical trials with a LOXL-2 targeting antibody [18] are in Phase II for fibrosis and beginning in cancer patients.…”

Spatially resolved microrheology of heterogeneous biopolymer hydrogels using covalently bound microspheres

“…Previous work using fibrosarcoma HT-1080 cells found that the matrix at the leading edge of a single cell undergoes reversible deformation during mesenchymal migration in 3D collagen matrix (Bloom et al 2008). Glioma cells were also found to secrete lysyl oxidase (LOX), a collagen crosslinker, promoting invasive behaviors (Laczko et al 2007;Cox et al 2013). Our results indicated that these modifications of the local network lead to the formation of a stiffer microenvironment at the leading edge of the mesenchymal migrating cell.…”