*3.3.5 HSP90*

HSP90 activates Hypoxia-inducible factor-1 and Nuclear Factor-κB which in turn regulate epithelial to mesenchymal transition, invasion and motility of CRC [89]. HSP90 has been shown in various studies to be overexpressed in CRC and may serve as a potential biomarker for CRC. In a small study of histological adenocarcinoma samples with an iTRAQ labeling method and QStar LC-MS/MS approach, a total of 82 altered proteins were found in CRC patients, which included overexpression of HSP90α and significant downregulation of Gelsolin. The results also suggested that HSP70 had decreased expression in the same samples [90]. Further validation using immunoprecipitation, MALDI-TOF-MS and immunoblotting confirmed that HSP90α is overexpressed in tumor cells and is correlated with poor prognosis and metastatic disease [91]. Plasma HSP90α serum levels were also significantly elevated in an analysis of 77 CRC patients compared to controls [92], thus highlighting the potential biomarker utility of this protein.

**147**

*Finding Needles in Haystacks: The Use of Quantitative Proteomics for the Early Detection…*

Matrix metalloproteinases (MMPs) are a diverse class of at least 25 zinc-dependent endopeptidases, which have important physiological applications and have also been implicated in the invasion, progression and metastasis of CRC. Accordingly, MMPs have been implicated as therapeutic targets, diagnostic and prognostic biomarkers. MMP subclasses have been demonstrated in various types of cancer, including breast

MMP1 functions to degrade type I, II and III collagen. MMP13 is structurally similar to MMP1, and likewise it also cleaves collagens, as well as degrading extracellular matrix proteins including fibrillar collagen, fibronectin, tenascin C and aggrecan core protein 1 [94]. Demonstration by immunostaining of 133 CRC samples showed that MMP1 expression was significantly correlated with hematogenous colorectal metastasis [95]. Increased expression is also associated with poor prognostic factors such as invasion level, lymph node and hepatic metastasis [96]. Similarly, MMP13 overexpression in CRC has also been shown to be associated with

The gelatinase group of MMPs also function to degrade the extracellular matrix; their main substrates being collagen and gelatin. Overexpression of MMP2 may promote CRC invasiveness due to its degradation of β1 integrins, thereby enhancing motility and decreasing cell adhesion [97]. Quantification of tumor, normal tissue and plasma samples using ELISA in 72 patients identified upregulation of MMP1, MMP2, MMP3 and MMP9 in carcinoma. MMP2 overexpression was also signifi-

MMP7 promotes tumor invasion by proteolytic cleavage of extracellular matrix proteins such as proMMP2 and proMMP9, and it is also involved in cellular proliferation and apoptosis regulation. Overexpression of MMP7 is found in 80% of CRC [99], and is associated with poor prognosis. This protein has been shown to have a sensitivity of greater than 92% to identify colonic adenomas in mouse models, Additionally mouse models have implicated overexpression of MMP7 in tumourigenesis [100, 101] whilst in humans, MMP7 has been implicated in progression of adenoma to carcinoma. Accordingly, MMP7 has been demonstrated in numerous studies using IHC to be

MMP12 is predominantly expressed in macrophages and degrades a wide range of substrates. MMP12 levels have been shown to be overexpressed in CRC, however this increased expression is associated with decreased risk of hepatic metastasis and decreased vascular endothelial growth factor expression [105, 106]. It is therefore postulated that MMP12 may have a protective role; a notion supported by a range of pro-tumourigenic effects being recorded following MMP12 inhibition [106, 107]. Conversely, along with MMP7 and MMP10, elevated serum levels of MMP12 have

overexpressed in adenoma and various stages of carcinoma [102–104].

been suggested to be associated with poor CRC prognosis [108].

*DOI: http://dx.doi.org/10.5772/intechopen.80942*

*3.4.1 MMP1 and MMP13: collagenases*

*3.4.2 MMP2 and MMP9: gelatinases*

cantly associated with lymph node metastasis [98].

poor prognosis [93].

*3.4.3 MMP7: matrilysin*

*3.4.4 MMP12: metalloelastase*

**3.4 Matrix metalloproteinases and their tissue inhibitors**

and melanoma, and therefore are not cancer specific biomarkers [93].

*Finding Needles in Haystacks: The Use of Quantitative Proteomics for the Early Detection… DOI: http://dx.doi.org/10.5772/intechopen.80942*
