Cutting to the Chase: How Matrix Metalloproteinase-2 Activity Controls Breast-Cancer-to-Bone Metastasis

Abstract

Bone metastatic breast cancer is currently incurable and will be evident in more than 70% of patients that succumb to the disease. Understanding the factors that contribute to the progression and metastasis of breast cancer can reveal therapeutic opportunities. Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes whose role in cancer has been widely documented. They are capable of contributing to every step of the metastatic cascade, but enthusiasm for the use of MMP inhibition as a therapeutic approach has been dampened by the disappointing results of clinical trials conducted more than 20 years ago. Since the trials, our knowledge of MMP biology has expanded greatly. Combined with advances in the selective targeting of individual MMPs and the specific delivery of therapeutics to the tumor microenvironment, we may be on the verge of finally realizing the promise of MMP inhibition as a treatment strategy. Here, as a case in point, we focus specifically on MMP-2 as an example to show how it can contribute to each stage of breast-cancer-to-bone metastasis and also discuss novel approaches for the selective targeting of MMP-2 in the setting of the bone-cancer microenvironment.

Bad to the Bone: The Role of the Insulin-Like Growth Factor Axis in Osseous Metastasis

“…Although not all the key players in the development of bone metastases are yet known, multiple molecules and signaling pathways appear to be important for metastasis. Indeed, in addition to the IGF pathway, NF-kB, matrix metalloproteases, and the Wnt, stromal cell-derived factor 1 (CXCL12)/C-X-C chemokine receptor type 4 (CXCR4) and PI3K/AKT signaling axes may also play key roles in the development and progression of bone metastases (39)(40)(41)(42)(43)(44)(45)(46).…”

Design and Structural Evolution of Matrix Metalloproteinase Inhibitors

“…[4] Since their discovery,M MPs have emerged as an intriguing target in pharmaceuticalr esearch. [5][6][7][8][9] Due to the involvement of members of the MMP family in am ultitude of severe diseases, such as cancer, [10][11][12][13][14][15][16] arthritis, [17,18] chronic obstructive pulmonary disease (COPD), [19][20][21] or sepsis, [22][23][24][25] great efforts weret aken to modulate MMP activity to possibly treat diseases in which MMP activity is out of balance. [26,27] Due to side effects evolving from al ack of selectivity and insufficient knowledge aboutt he relevance of the target family in pathological processes, no compound designed as an MMP inhibitor has reached the market so far,a nd clinicalt rials have failed.…”

TIMP-2 inhibits metastasis and predicts prognosis of colorectal cancer via regulating MMP-9

“…Tissue inhibitors of metalloproteinases (TIMPs) are endogenous proteins which could prohibit cell proliferation and migration by inhibiting the function of Matrix metalloproteinases (MMPs). Previous studies have shown that when the balance between TIMPs and MMPs was disrupted, it could lead to the degradation of the extracellular matrix and induce tumor cell invasion, migration or other receptor-mediated changes [5]. Tissue inhibitor of metalloproteinase-2 (TIMP-2) is a unique inhibitor among the TIMP family members, because it not only correlates with matrix remodeling and angiogenesis suppressing but also involves in the process of tumor growth, inflammation, and other diseases [6].…”