Jian Cao

Bio: Jian Cao is an academic researcher from Stony Brook University. The author has contributed to research in topics: Matrix metalloproteinase & Cell migration. The author has an hindex of 32, co-authored 62 publications receiving 4001 citations. Previous affiliations of Jian Cao include State University of New York System.

Critical appraisal of the use of matrix metalloproteinase inhibitors in cancer treatment

Abstract: Experimental studies performed prior to 1990 led to the widely held belief that matrix metalloproteinases (MMPs) produced by cancer cells are of critical importance in tumor invasion and metastasis. Based on this evidence, the pharmaceutical industry produced several well tolerated, orally active MMP inhibitors (MMPIs) which demonstrated efficacy in mouse cancer models. Phase III clinical trials initiated in 1997-98 using marimastat, prinomastat (AG3340), and BAY 12-9566 alone or in combination with standard chemotherapy in patients with advanced cancers (lung, prostate, pancreas, brain, GI tract) have recently been reported; no clinical efficacy was demonstrated. Bayer and Agouron have discontinued their ongoing Phase III drug trials of MMPIs in advanced cancer. In retrospect, the failure of MMPIs to alter disease progression in metastatic cancer might have been anticipated since MMPs appear to be important in early aspects of cancer progression (local invasion and micrometastasis) and may no longer be required once metastases have been established. Our understanding of MMP pathophysiology in cancer has expanded considerably in the past 10 years. Current views indicate that: (1) most MMPs in tumors are made by stromal cells, not carcinoma cells; (2) cancer cells induce stromal cells to synthesize MMPs using extracellular matrix metalloproteinase inducer (EMMPRIN) and cytokine stimulatory mechanisms; and (3) MMPs promote cell migration and the release of growth factors sequestered in the extracellular matrix. MMPs have a dual function in tumor angiogenesis: MMP-2 and MT1-MMP are required in breaking down basement membrane barriers in the early stage of angiogenesis, while other MMPs are involved in the generation of an angiogenic inhibitor, angiostatin. In spite of considerable recent progress in identifying multiple roles of MMPs in disease, our understanding of MMP function in cancer is far from complete (see Table 1). Based on accumulated data, it is recommended that future MMPI trials focus on: (1) patients with early stage cancer; (2) the use of MMPIs along with chemotherapy; (3) the measurement of MMPs in tumor tissue and blood as a means of identifying patients who are more likely to respond to MMPI therapy; and (4) identification of biomarkers that reflect activation or inhibition of MMPs in vivo.

Targeting Matrix Metalloproteinases in Cancer: Bringing New Life to Old Ideas

Abstract: Since the identification of matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases, as being a driving factor for cancer progression and patient prognosis, MMPs have been studied extensively. Although early programs targeting MMPs were largely unsuccessful in clinical trials, they remain a viable and highly desirable therapeutic target based on preclinical studies and their role in disease progression. As information regarding the structure and function of these proteinases is compiled and biotechnology evolves, tools to develop better inhibitors are within our grasp. Improved methods for high throughput screening and in silico drug design programs have identified compounds which are highly potent, have high binding affinities, and exhibit favorable pharmacokinetic profiles. More recently, advances in drug delivery methods or compounds which bind outside the active site have brought new light to the field. In this review, we highlight the role of MMPs in cancer, clinical trials for MMP inhibitors, and novel approaches to targeting MMPs in cancer.

Membrane type-matrix metalloproteinases (MT-MMP).

Abstract: Publisher Summary Matrix metalloproteinases (MMPs) belong to the family of zinc endopeptidases collectively referred to as metzincins. The metzincin superfamily is distinguished by a highly conserved motif containing three histidines that bind zinc at the catalytic site and a conserved methionine that sits beneath the active site. The metzincins are subdivided into four multigene families: serralysins, astacins, ADAMs/adamalysins, and MMPs. Once activated, MMPs degrade a variety of extracellular matrix components and assorted other proteins including growth factors, growth factor binding proteins, and protease inhibitors. The ability to degrade extracellular matrix proteins is essential for any cell to interact properly with its immediate surroundings and for multicellular organisms to develop and function normally. MMPs also generate matrix protein fragments, which have functional activity of their own. These various functions of MMPs modulate cell invasion and metastasis, cell migration, apoptosis, and angiogenesis. The belief that an MMP is involved in a given biologic/pathologic process is often based on the strength of its association with that process and the existence of plausible mechanisms that can be tested by experimental approaches. Because of extensive redundancy of MMP function in animals, it has been difficult to appreciate the role of individual genes in various experimental models. The multiplicity of MMPs with distinct but somewhat overlapping functions appears to act as a safeguard against loss of regulatory control. The known MMP genes have been divided into four subfamilies based on gene structure. Group I consists of the collagenase subfamily. Group 2 consists of the gelatinases/modular alteration (fimodular a-like domains) subfamily. Group 3 consists of the variant hemopexin exon subfamily. Group 4 consists of the variant catalytic exon and unique 3′-end exon (plasma membrane and cytoplasmic domains) subfamily, which consists of the membrane type-matrix metalloproteinases (MT-MMPs).

Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry.

Abstract: Matrix metalloproteinases (MMPs), also designated matrixins, hydrolyze components of the extracellular matrix. These proteinases play a central role in many biological processes, such as embryogenesis, normal tissue remodeling, wound healing, and angiogenesis, and in diseases such as atheroma, arthritis, cancer, and tissue ulceration. Currently 23 MMP genes have been identified in humans, and most are multidomain proteins. This review describes the members of the matrixin family and discusses substrate specificity, domain structure and function, the activation of proMMPs, the regulation of matrixin activity by tissue inhibitors of metalloproteinases, and their pathophysiological implication.

How Matrix Metalloproteinases Regulate Cell Behavior

Abstract: ▪ Abstract The matrix metalloproteinases (MMPs) constitute a multigene family of over 25 secreted and cell surface enzymes that process or degrade numerous pericellular substrates. Their targets include other proteinases, proteinase inhibitors, clotting factors, chemotactic molecules, latent growth factors, growth factor–binding proteins, cell surface receptors, cell-cell adhesion molecules, and virtually all structural extracellular matrix proteins. Thus MMPs are able to regulate many biologic processes and are closely regulated themselves. We review recent advances that help to explain how MMPs work, how they are controlled, and how they influence biologic behavior. These advances shed light on how the structure and function of the MMPs are related and on how their transcription, secretion, activation, inhibition, localization, and clearance are controlled. MMPs participate in numerous normal and abnormal processes, and there are new insights into the key substrates and mechanisms responsible for regula...

Targeting RAS signalling pathways in cancer therapy

Abstract: The RAS proteins control signalling pathways that are key regulators of several aspects of normal cell growth and malignant transformation. They are aberrant in most human tumours due to activating mutations in the RAS genes themselves or to alterations in upstream or downstream signalling components. Rational therapies that target the RAS pathways might inhibit tumour growth, survival and spread. Several of these new therapeutic agents are showing promise in the clinic and many more are being developed.

Tumour-cell invasion and migration: diversity and escape mechanisms

Abstract: Cancer cells possess a broad spectrum of migration and invasion mechanisms. These include both individual and collective cell-migration strategies. Cancer therapeutics that are designed to target adhesion receptors or proteases have not proven to be effective in slowing tumour progression in clinical trials — this might be due to the fact that cancer cells can modify their migration mechanisms in response to different conditions. Learning more about the cellular and molecular basis of these different migration/invasion programmes will help us to understand how cancer cells disseminate and lead to new treatment strategies.