Some Major Biomarkers Related To Multistage Carcinogenesis

While numerous antioxidative vitamins and phytochemicals have been found to exert potential cancer chemopreventive activities, the definition of the appropriate biomarkers to quantify their chemopreventive effects remains subjective.18 The precise understanding of biochemical and molecular mechanisms is the first step to identifying such proper biomarkers and is essential for the successful implementation of chemopreventive strategies.

Cellular enzymes and structural proteins, membranes, simple and complex sugars, and DNA and RNA are all susceptible to oxidative damage that may lead to tumor initiation. The elimination or minimization of exposure to diverse environmental carcinogens is one strategy for preventing the majority of human cancers, but the complete avoidance of exposure to etiologic factors that can initiate cancer may be unrealistic.1 Therefore, recent chemopreventive strategies have focused more on identifying substances possessing antipromoting or antiprogressive activities that can suppress the transformation of initiated or precan-cerous cells into malignant ones, rather than searching for anti-initiators.1

A promising strategy applicable to the identification and development of chemopreventive agents is the inhibition of inflammation. Cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) are important enzymes that mediate inflammatory processes. Improper upregulation of COX-2 and/or iNOS is associated with the pathophysiology of certain types of human cancers as well as with inflammatory disorders. Tumor promoters and lipopolysaccharide can induce inflammation through the overexpression of COX-2 and iNOS with the concomitant generation of ROS and RNS. Because inflammation is closely linked to tumor promotion, substances with potent anti-inflammatory activities are anticipated to exert chemopreventive effects on carcinogenesis, particularly in the promotion stage.

GJIC is essential for maintaining the homeostatic balance by modulating cell proliferation and differentiation in multicellular organisms.19 Most normal cells have functional GJIC, while most cancer cells have dysfunctional GJIC.20 A consistent observation is that tumor promoters21-24 inhibit GJIC, while antitumor-promoting agents2526 and anticancer drugs27 can reverse the downreg-ulation of GJIC.20 Because the inhibition of GJIC is strongly related to carcinogenicity, particularly tumor promotion, enhancers of GJIC are also anticipated to prevent cancer.

The inhibition of angiogenesis is considered another prospective strategy in both cancer chemoprevention and therapy, because angiogenesis is an essential process of most cancers. MMPs are enzymes involved in degradation of the extracellular matrix (ECM) and are linked to various steps in the development of metastasis.28 Therefore, MMPs have been the main target of an increasing number of clinical trials approved for testing the tolerance and therapeutic efficacy of antiangiogenic agents. Although MMPs have long been implicated in cancer-cell invasion and metastasis, recent reports suggest that MMPs are also linked to the tumor promotion process.29-32 Therefore, the inhibition of MMP production may be associated with antitumor-promoting activities as well as antiangiogenic and antimetastatic activities. Thus, the inhibition of inflammation, enhancement of GJIC, and inactivation of MMP are considered important bio-markers in blocking tumor promotion and tumor progression processes in multistage carcinogenesis.

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