MMP-1 is a Prognostic Marker for Hematogenous Metastasis of Colorectal Cancer

Sunami, Eiji; Tsuno, Nelson H.; Osada, Takuya; Saito, Shinsuke; Kitayama, Joji; Tomozawa, Shigeru; Tsuruo, Takashi; Shibata, Yoichi; Muto, Tetsuichiro; Nagawa, Hirokazu

doi:10.1634/theoncologist.5-2-108

Cited by 119 publications

(74 citation statements)

References 42 publications

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“…Earlier, Murray et al 7 showed that high MMP-1 expression was associated with poor prognosis, but only 16% of the tumors were immunoreactive. High MMP-1 expression has been related to hematogenous metastasis, 42 and increasing depth of invasion and metastasis 43 in CRC. Likewise, weak MMP-1 expression has been related to a better prognosis of patients with advanced CRC.…”

Section: Discussionmentioning

confidence: 99%

Prognostic significance of matrix metalloproteinases‐1, ‐2, ‐7 and ‐13 and tissue inhibitors of metalloproteinases‐1, ‐2, ‐3 and ‐4 in colorectal cancer

Hilska

Roberts

Collan

et al. 2007

Intl Journal of Cancer

133

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Strong expression of many matrix metalloproteinases (MMPs) has been related to poor survival of colorectal cancer (CRC) patients. The expression of tissue inhibitors of metalloproteinases (TIMPs) has been associated with both a beneficial and a poor outcome and there is thus a need to further clarify the significance of MMPs and TIMPs in CRC. The prognostic significance of 4 MMPs and TIMPs in CRC was evaluated. Formalinfixed, paraffin-embedded tissue arrayed samples of 351 patients with primary colon or rectal cancer of Dukes' stages A-D were selected for immunohistochemical staining of MMP-1, -2, -7 and -13, and TIMP-1, -2, -3 and -4. High expression of MMP-2 in the malignant epithelium as well as in the surrounding stroma was associated with reduced survival of colon cancer patients. Strong epithelial and stromal cytoplasmic staining of TIMP-3 was associated with a longer survival in rectal cancer patients, and here the interobserver variation for evaluating the degree of staining was lower than for epithelial staining. Strong stromal cytoplasmic staining of TIMP-4 predicted longer survival of rectal cancer patients. Multivariate analysis showed that stromal cytoplasmic TIMP-3 staining was the only marker of independent prognostic value. MMP-2 might be a useful prognostic marker in colon cancer, and TIMP-3 and TIMP-4 in rectal cancer, but the findings associated with stromal staining should be interpreted with some caution. Different biologic behavior or different genetic development may explain the differences between colon and rectal cancers regarding the expression of MMP-2, TIMP-3 and TIMP-4. ' 2007 Wiley-Liss, Inc.Key words: colorectal cancer; matrix metalloproteinases; tissue inhibitors of metalloproteinases; prognosis; survival Matrix metalloproteinases (MMPs) are a large family of zincdependent neutral endopeptidases that play an important role in the degradation of all matrix components crucial for malignant tumor growth, invasion and metastasis. 1,2 Metalloproteinases are inhibited by tissue inhibitors (TIMPs) which are secreted proteins. These bioactive substances are specific inhibitors of MMPs that bind to enzymatically active MMPs at a 1:1 molar stoichiometry thus inhibiting proteolysis. 3 The role of TIMPs for the homeostasis of the extracellular matrix is critical and may inhibit or stimulate tumorigenesis. 4 Many studies have shown that the expression of several MMPs is enhanced in a number of malignancies, including colorectal cancer (CRC), but the relation between the expression of MMPs and overall patient survival is not clear. 5,6 Enhanced expression of MMP-1, -7 and -13 has been reported to be associated with metastasis and poor survival of patients with CRC. 7-9 Tissue concentrations of MMP-1, MMP-2 and TIMP-1 are increased in CRC compared to healthy colorectal tissue. This has been related to the role of these endogenous substances in cancer progression. 2 Healthy tissue may contain high levels of TIMP-2 10 and the levels of TIMP-3 mRNA are regionally increased in moderately and poorl...

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Section: Discussionmentioning

confidence: 99%

Prognostic significance of matrix metalloproteinases‐1, ‐2, ‐7 and ‐13 and tissue inhibitors of metalloproteinases‐1, ‐2, ‐3 and ‐4 in colorectal cancer

Hilska

Roberts

Collan

et al. 2007

Intl Journal of Cancer

133

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“…This has been shown with MMP-2 in breast cancer 66 and with MMP-1 in colorectal cancer. 67 In some studies, MMP determinations from patient serum have shown predictive value in estimation of metastasis risk. High serum levels of MMP-2 correlate with the presence of metastases in lung cancer 68 or to disease progression in patients with prostate cancer, 69 and a high serum MMP-9/E-cadherin ratio can predict metastasis of renal cell carcinoma.…”

Section: Mmps As Predictors Of Recurrence or Metastasis Riskmentioning

confidence: 99%

Matrix metalloproteinases in cancer: Prognostic markers and therapeutic targets

Vihinen

Kähäri

2002

Intl Journal of Cancer

581

484

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Degradation of extracellular matrix is crucial for malignant tumour growth, invasion, metastasis and angiogenesis. Matrix metalloproteinases (MMPs) are a family of zinc-dependent neutral endopeptidases collectively capable of degrading essentially all matrix components. Elevated levels of distinct MMPs can be detected in tumour tissue or serum of patients with advanced cancer and their role as prognostic indicators in cancer is studied. In addition, therapeutic intervention of tumour growth and invasion based on inhibition of MMP activity is under intensive investigation and several MMP inhibitors are in clinical trials in cancer. In this review, we discuss the current view on the feasibility of MMPs as prognostic markers and as targets for therapeutic intervention in cancer.

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“…Desde então, as MMPs estão relacionadas a mais de 25 tipos de enzimas zinco-dependentes que compartilham domíni-os funcionais comuns, tendo seus nomes descritivos associados a um substrato preferencial, e a um sistema de numeração dentro da família MMP, baseados em sua ordem de descobrimento 5,40,61 . Desta forma, a colagenase intersticial é também denominada de Metaloproteinease-1 (MMP-1) e degrada, especificamente, os colágenos tipo I, II e III 28,62 . Estas enzimas são codificadas por diferentes genes, e produzidas por uma variedade de tipos celulares, incluindo células epiteliais, mesenquimais, inflamatórias e neoplásicas 63 .…”

Section: Matriz Metaloproteinase-1 E Câncer Colorretalunclassified

“…Enquanto todas MMPs secretadas são normalmente liberadas como proenzimas, a MMP-1 pode ser liberada como enzima ativa antes de chegar à superfície celular 63 , tendo papel fundamental na remodelação da MEC, degradando diretamente vários de seus componentes e indiretamente ativando a pró-metaloproteinase-2 35 . A presença deste tipo de MMP em espécimes de CCR tem sido associada com um pior prognóstico, independentemente do estadiamento de DUKES 5,27,28,55,56,61,67 …”

Section: Matriz Metaloproteinase-1 E Câncer Colorretalunclassified

Metaloproteinases 1 e 7 e câncer colorretal

Júca

Nunes²,

Menezes³

et al. 2008

Rev bras. colo-proctol.

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RESUMO: A metaloproteinase-1 (MMP-1) e a metaloproteinase-7 (MMP-7) são proteinases da matriz extracelular (MEC), zincodependentes, envolvidas no processo inicial da carcinogênese por permitirem a invasão tumoral na célula e promover o processo INTRODUÇÃOA invasão celular de um tecido pode ocorrer durante vários estágios, sejam fisiológicos ou patológi-cos. Existem barreiras que se opõem ao movimento de invasão tecidual, como as membranas basais, a matriz estromal e a junção entre as células. Acredita-se que um mecanismo comum para a quebra destas barreiras, seja a atuação de enzimas proteolíticas. Os tipos de proteinases envolvidas dependem do tipo de tecido envolvido e das circunstâncias encontradas na matriz. Não obstante, existem três classes de proteinases (matriz metaloproteinases -MMP, serina proteinases e cisteína proteinases) que têm distribuição alterada, aumento na expressão e/ou atividade, envolvidas na remodelação da matriz, facilitando a invasão tumoral. Algumas evidências sugerem que proteinases, especificamente as MMPs, estão envolvidas nos estados iniciais da progressão tumoral 1 .A carcinogênese e o desenvolvimento do cân-cer colorretal são processos de várias etapas, caracterizadas por mudanças progressivas na quantidade ou atividade de proteínas que regulam a proliferação, diferenciação e sobrevida celular, e são mediados por mecanismos genéticos e epigenéticos 2, 3 . Uma seqüên-cia ordenada de eventos não aleatórios leva ao desenvolvimento do câncer colorretal (CCR), passando o epitélio por transformação invasiva 4 , sendo a progressão do epitélio intestinal normal até o desenvolvimento do carcinoma invasivo estimada entre 7 e 12 anos 5 . A membrana basal e a matriz extracelular representam duas barreiras físicas à invasão maligna, e suas degradações pelas MMPs têm papel fundamental na progressão tumoral e disseminação das metástases 4,[6][7][8][9][10][11] .

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MMP-1 is a Prognostic Marker for Hematogenous Metastasis of Colorectal Cancer

Cited by 119 publications

References 42 publications

Prognostic significance of matrix metalloproteinases‐1, ‐2, ‐7 and ‐13 and tissue inhibitors of metalloproteinases‐1, ‐2, ‐3 and ‐4 in colorectal cancer

Prognostic significance of matrix metalloproteinases‐1, ‐2, ‐7 and ‐13 and tissue inhibitors of metalloproteinases‐1, ‐2, ‐3 and ‐4 in colorectal cancer

Matrix metalloproteinases in cancer: Prognostic markers and therapeutic targets

Metaloproteinases 1 e 7 e câncer colorretal

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