Matrix metalloproteases in head and neck cancer

Abstract

Matrix metalloproteases (MMPs) are a collection of enzymes capable of cleaving extracellular matrix components, growth factors, and cell-surface receptors. MMPs modulate most aspects of tumorigenesis and are highly expressed in cancer compared with normal tissues. Preclinical studies have demonstrated that head and neck squamous cell carcinomas (HNSCCs) express high levels of MMPs in vivo and that inhibition of these enzymes in vitro and in mouse models decreases invasion and metastasis. However, the clinical trials for MMP inhibitors have failed to demonstrate a significant survival advantage in most cancers. The disparity between preclinical and clinical studies has led to the reevaluation of how MMP functions in cancer and the design of clinical trials for molecularly targeted agents. Mouse model data and analysis of HNSCC tumor specimens suggests that membrane type-1 MMP (MT1-MMP) may be a critical enzyme in tumor cell invasion and survival in vivo. This accumulated data provide evidence for development of selective MT1-MMP inhibitors as therapy in HNSCC.Keywords matrix metalloprotease inhibitor; MMP; extracellular matrix; head and neck cancer; squamous cell carcinoma; membrane type-1 MMP; drug development; proteases The hallmark of cancer remains regional and distant metastases. Regional metastasis in head and neck squamous cell carcinoma (HNSCC) decreases survival by almost 50%, and invasion beyond the lymph node capsule further decreases survival. 1 For tumor cells to invade and metastasize they must: (1) develop motility, (2) alter cell-cell and cell-matrix adhesion, and (3) remodel the extracellular matrix. 2 It was recognized in the 1980s that matrix metalloprotease (MMP) could degrade extracellular matrix (ECM) components and that this could potentiate local tumor invasion and metastasis. 3 A significant amount of effort has been funneled into the development of MMP inhibitors (MPIs) promote tumor angiogenesis by mobilizing or activating factors such as basic fibroblast growth factor, vascular endothelial growth factor, or transforming growth factor-beta. 15,16,18 Second, the complexity of cell types expressing MMPs in the tumor mass was appreciated ( Figure 1 ASSESSMENT OF MATRIX METALLOPROTEASES IN HEAD AND NECK CANCERMMPs consistently found overexpressed in head and neck cancer include MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-11, MMP-13, and MMP-14 (Table 1). However, MMP-1, MMP-2, MMP-9, and MT-1 MMP are most commonly identified in HNSCC and associated with disease progression. With the understanding that conflicting reports are abundant and negative studies unlikely to be published, it is possible to summarize the extensive MMP findings in HNSCC. Although most studies evaluate only one or two MMPs within a given head and neck site, studies have examined expression of multiple TIMPs and MMPs in oral cavity SCC. 12,22 Interestingly, these studies commonly identify upregulation of TIMP-1, which is associated with a poor survival. Levels of TIMP-2 are often unchanged between t...

Comparative analysis of the immunohistochemical expression of collagen IV, MMP-9, and TIMP-2 in odontogenic cysts and tumors

“…24,25 Preclinical trials have shown that squamous cell carcinomas express high levels of MMPs in vivo and that the inhibition of these enzymes in vitro and in animal models reduces the invasion potential and metastatic capacity of the tumor. 2 Regarding the expression of MMP-9 in odontogenic cysts and tumors, in the present study epithelial and mesenchymal cells of the lesions studied diffusely secreted this protein. This finding suggests a role of MMP-9 in tumor growth, because the protein is known to act on the remodeling of ECM and the degradation of bone matrix.…”

“…In the case of tumors, this situation contributes to the growth and higher aggressiveness of the tumor. 2 The odontogenic keratocyst, recently reclassified as keratocystic odontogenic tumor (KOT), 3 is known for its aggressive nature and high rate of recurrence, especially compared with other odontogenic cysts. 4 Ameloblastoma is a locally aggressive benign epithelial odontogenic tumor with a marked invasion potential that results in multiple recurrences after enucleation and curettage.…”

Immunohistochemical expression of MMP-9 and VEGF in squamous cell carcinoma of the tongue

“…Preclinical trials have shown that SCCs express high levels of MMPs in vivo and that inhibition of these enzymes in vitro and in animal models is associated with invasiveness and metastasis (14). However, other studies were unable to confirm these results (4,9).…”

Gene alterations in head and neck carcinomas and their role in promoting malignant behavior (Review)

“…MMP inhibitors may also fail as monotherapy, as they have little cytotoxic effects. Dosing was limited by musculoskeletal side effects, and thus it remains unclear whether other modalities of applying the medication could be beneficial (55).…”