Stromal matrix metalloprotease-13 knockout alters Collagen I structure at the tumor-host interface and increases lung metastasis of C57BL/6 syngeneic E0771 mammary tumor cells

Abstract

BackgroundMatrix metalloproteases and collagen are key participants in breast cancer, but their precise roles in cancer etiology and progression remain unclear. MMP13 helps regulate collagen structure and has been ascribed largely harmful roles in cancer, but some studies demonstrate that MMP13 may also protect against tumor pathology. Other studies indicate that collagen’s organizational patterns at the breast tumor-host interface influence metastatic potential. Therefore we investigated how MMP13 modulates collagen I, a principal collagen subtype in breast tissue, and affects tumor pathology and metastasis in a mouse model of breast cancer.MethodsTumors were implanted into murine mammary tissues, and their growth analyzed in Wildtype and MMP13 KO mice. Following extraction, tumors were analyzed for collagen I levels and collagen I macro- and micro-structural properties at the tumor-host boundary using immunocytochemistry and two-photon and second harmonic generation microscopy. Lungs were analyzed for metastases counts, to correlate collagen I changes with a clinically significant functional parameter. Statistical analyses were performed by t-test, analysis of variance, or Wilcoxon-Mann–Whitney tests as appropriate.ResultsWe found that genetic ablation of host stromal MMP13 led to: 1. Increased mammary tumor collagen I content, 2. Marked changes in collagen I spatial organization, and 3. Altered collagen I microstructure at the tumor-host boundary, as well as 4. Increased metastasis from the primary mammary tumor to lungs.ConclusionsThese results implicate host MMP13 as a key regulator of collagen I structure and metastasis in mammary tumors, thus making it an attractive potential therapeutic target by which we might alter metastatic potential, one of the chief determinants of clinical outcome in breast cancer. In addition to identifying stromal MMP13 is an important regulator of the tumor microenvironment and metastasis, these results also suggest that stromal MMP13 may protect against breast cancer pathology under some conditions, a finding with important implications for development of chemotherapies directed against matrix metalloproteases.

Second-harmonic generation scattering directionality predicts tumor cell motility in collagen gels

“…Furthermore, we have previously shown that altering the availability of stromal MMP-13 altered F/B and metastatic output. 18 The fact that tumor cells themselves can affect F/B (as shown here), and that alteration of enzymes present in the stroma can alter F/B (as shown previously), suggests that both tumor and stromal cells play key roles in defining the matrix microstructure that dictates F/B.…”

CCR4 promotes metastasis via ERK/NF-κB/MMP13 pathway and acts downstream of TNF-α in colorectal cancer

“…It has been reported that MMP13 is related to cancer aggressiveness in hepatocellular carcinoma [27]. Stromal MMP13 mediates tumor microenvironment and promotes lung metastasis of breast cancer [28]. In the present study, expression level of MMP13 was found to be decreased under condition of CCR4 knockdown, while overexpression of CCR4 increased the level of MMP13 in tumor cells.…”

CCL17‐CCR4 axis promotes metastasis via ERK/MMP13 pathway in bladder cancer

“…It has been reported that MMP13 is involved in cancer metastasis in hepatocellular carcinoma . Stromal MMP13 is involved in tumor microenvironment and promotes lung metastasis of breast cancer . In our study, expression level of p‐ERK and MMP13 was found to be decreased under conditions of CCR4 knockdown in BC cells.…”