Review
Apoptosis and colorectal cancer: implications for therapy

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Colorectal cancer (CRC) is characterized by the partial suppression of apoptosis, which in turn gives tumours a selective advantage for survival and can cause current chemotherapy approaches to be ineffective. Recent progress in understanding the mechanisms of apoptosis in colorectal carcinogenesis has provided potential new targets for therapy. Here, we review recent studies of the regulation of apoptosis and its role in CRC initiation and progression, and we discuss the relationship between chemoresistance and the suppression of apoptosis. Recent progress in targeting apoptotic pathways and their regulators provide strategies for the exploration of novel therapies for CRC.

Introduction

Colorectal cancer (CRC) is the third most common cause of cancer-related death among men and women in the western world 1, 2. Europe has the highest CRC incidence, with an estimated 412 900 new cases in 2006 [1], closely followed by the USA, which expected 145 290 new CRCs in 2008 [3]. CRC is rare in Asia, Africa and parts of South America. Although no age group is unaffected, the disease occurs mainly in the seventh decade of life. At the time of presentation, ∼40% of patients already have distant metastases. 5-fluorouracil (5-FU)-based chemotherapeutic regimens are the most common treatments for these patients. Although combining 5-FU with irinotecan and oxaliplatin has improved the response rate, chemotherapies are usually not highly effective against disseminated CRC. A new therapeutic strategy is therefore needed for the treatment of advanced or metastatic CRCs.

Progressive inhibition or evasion of apoptosis has been found during the transformation of colorectal epithelium to carcinoma [4], indicating that dysfunction of apoptosis has an important role in colorectal tumorigenesis. When programmed cell death does not occur appropriately in colon, cells that should be eliminated might persist, become immortal and subsequently develop into colorectal tumours. The cytotoxic action of most chemotherapeutic drugs is often mediated by the activation of apoptotic pathways [5]; therefore, any defect, dysfunction or altered expression of genes encoding key apoptotic proteins can produce drug resistance. For example, loss of p53 function by mutation disables apoptosis and accelerates tumour development, and the altered expression of pro-apoptotic B-cell lymphoma (Bcl)-related proteins dramatically changes the sensitivity of cancer cells to chemotherapy [6]. It is apparent that defects in apoptosis underpin both colorectal tumorigenesis and drug resistance. The search for new therapeutic approaches for the management of metastatic colon cancers has led us to revisit apoptosis and its role in colon cancer tumorigenesis. Recent progress in understanding the molecular mechanisms and role of apoptosis in colon cancer development has provided novel targets for therapy. Here, we review studies of the molecular mechanisms of apoptosis in CRC initiation and progression, and evaluate factors that affect and regulate apoptosis in CRC. Furthermore, dysfunctions in apoptotic pathways through which CRC can develop resistance to chemotherapy are discussed, and potential therapeutic targets are suggested. It is hoped that molecular therapies targeting apoptotic pathways might have the potential to provide new approaches for CRC treatment.

Section snippets

Apoptosis in the normal colorectum

Apoptosis has an important role in determining the architecture of normal colonic epithelia and is part of the response to stress [7]. Each colonic crypt contains several thousand differentiated cells and a small number of stem cells. Although there are different views regarding the origin of tumour cells in colonic crypts 8, 9, colonic stem cells are predominantly found at the bottom of the crypts and divide slowly [10]. Differentiated cells divide rapidly and travel to the top of the crypt;

Apoptosis and colorectal carcinogenesis

The transformation of colorectal epithelium to carcinoma is associated with a progressive inhibition of apoptosis [16], and usually proceeds through a series of pathological progressions to produce colorectal polyps, adenomas, adenoma-containing carcinomas and adenocarcinomas [17]. Examination of the cellular proliferation and apoptosis levels in these processes has shown that both increased proliferation and decreased apoptosis occur during CRC development [18]. The APC and β-catenin pathway

Transforming growth factor-β

Transforming growth factor-β (TGF-β) is a member of a growth factor superfamily that regulates cellular proliferation, differentiation, apoptosis and extracellular matrix formation [38]. TGF-β acts as a tumour suppressor in the normal colon by inhibiting cell proliferation and inducing apoptosis [39]. Disruption of TGF-β signalling is predominantly due to mutational inactivation of the TGF-β receptor (TGFBR2) that occurs in ∼30% of CRC [40]. The mechanism of TGF-β-induced apoptosis has not been

Apoptosis and chemoresistance in CRCs

Even after chemotherapy, metastases can still spread owing to cancer cell resistance. This is a major contributor to the limited effectiveness of current chemotherapeutic drugs. Cancer cells use many mechanisms to protect themselves against the damaging effects of chemotherapeutic agents. For instance, some cancer cells can reduce intracellular drug accumulation by increasing drug efflux from cells and decreasing drug influx. Some cancer cells can reduce drug-related damage by modifying drug

New strategies for the development of CRC treatments

Although not all conventional drugs have been designed to induce apoptosis directly, most of these agents do in fact kill cancer cells through apoptotic pathways, either directly or indirectly. Drugs that directly induce apoptosis have several advantages over those that do not directly cause apoptosis. First, apoptosis results in removal of dead cells in an inconspicuous way, involving phagocytosis by neighbouring cells or specialized macrophage-like cells without producing inflammation and

Concluding remarks

Alteration or suppression of apoptosis has an important role in CRC initiation and development. Aberration of intrinsic apoptotic components, mutation of tumour suppressor genes, modification of COX-2 and PGE2, NF-κB pathways and dependence receptors all contribute to the suppression of apoptosis in CRC development. Targeting these molecules and pathways to induce cancer cell death might offer an alternative approach for treating CRC with the potential advantages of specifically targeting

Glossary

Intrinsic apoptotic pathway
the activation of programmed cell death by intracellular signals that are mediated by the Bcl protein family, resulting in the release of cytochrome c from the mitochondrial membrane, and the subsequent activation of caspase-9 and downstream effectors caspases, such as caspase-3 and -7.
Extrinsic apoptotic pathway
the activation of programmed cell death by interaction between ‘death ligands’ and ‘death receptors’, in which caspase-8 is activated. When death ligands bind

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