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Molecular basis of cancer initiation.


Cancer is used to describe cells with abnormal, uncontrolled and uncoordinated growth that results in formation of a mass or swelling. Cancer is recognised as a public health problem especially in developed countries [1]. Available data shows that approximately 1.5 million new cases were diagnosed in United State of America in 2009, while an estimated death of 562340 occurred due to cancer in the same year in United State of America [1]. The causes of cancer are not completely understood, however, studies have highlighted some contributing factors; these include race, ethnicity, socioeconomic status and environment etc; for example, while American men of African origin have 18 % increased risk of developing cancer compared to white men, women of African descends are less likely to develop cancer than women of white origin [2]

In addition, data from a most recent study indicates that the burden of cancer will rise sharply over the next decades due to the geometric increase in the aging population [3]. This means that the next decades will see upsurge in the number of people diagnosed with cancer of various types across the globe; and an increased burden on the health facilities. The simple question is;--how is cancer initiated? What controls its progression and metastasis? Over many centuries this question remains unresolved despite huge amount spent in cancer research. But if the right answers are known, such knowledge would be important in prevention and curative treatment of cancer, and thus justifies unrelenting works in understanding the process of carcinogenesis. The aim of the current study is to review the current understanding of biology of cancer initiation and progression.


Cancer arises from a cell that has acquired genetic mutations in key genes controlling the cell cycle, cell death pathways, DNA repair. Subsequently, tumours will evolve to contain cytogenetically different clones as a result of genetic instability caused by the initial mutations [4], [5]. It has been shown that chromosomal instability is an important feature of many forms of cancer [6]. Recently, it has become clear that double stranded DNA breaks (DSB) and repair enzyme abnormalities can contribute to the carcinogenesis. In fact, there are evidences suggesting that dysregulation of enzymes responsible for repair of the DNA breaks can introduce lesions which may lead to widespread genomic instability and subsequently results in cancer [7]. This may happen when DNA strand break occurs and the damage is not repaired and bypassed, if the cell cycle progresses either due to abnormalities in P53 signalling pathways, the resulting cell clones are bound to have inherited some forms of genomic perturbations. The study of Robbiani et al [7] demonstrated an association between DNA damage response pathways and the development of B-cell lymphoma in cells over-expressing activation-induced cytidine deaminase (AID). B cells expand their receptor repertoire by rearrangements at the Igh locus; this process involves two prominent mechanisms: V(D)J recombination in developing B cells and class switch recombination in mature B cells. These rearrangements are promoted by two elements, the intronic enhancer (iE[micro]) in V(D)J recombination and the Igh3' RR in class switch recombination. It is known that the action of AID may result in generation of DSB especially in the immunoglobin (Ig) genes responsible for class switch recombination--this type of damage often lead to development of reciprocal chromosomal translocation and lymphoma [8]. Usually, DSB would induce expression and activation of gamma H2AX at the site of the break, which upon ubiquitilization initiates recruitment of repair proteins to the site of the damage [9]. Immediately after the damage is repaired; often by the homologous recombination pathway (error free) or the non homologous end join repair pathway (error prone), the gamma 2HAX disappears. It is now understood that ubiquitilation process plays important role in regulating DSB repair, and that perturbation of its control molecules including Small ubiquitin-related modifier (SUMO), E3 ligase (such as PIAS1 and PIAS4) may induce impaired DNA DSB repair [10]. It is recognised that such abnormalities in any of the repair pathways may result in severe genomic instability and aggressive cancer progression. This form of abnormality has been reported in breast cancer, prostate cancer, lung cancer and colon cancer. It's long been known that some environmental factors such as UV light, dietary products like amino-1- methyl-6-phenylimidazo [4,5-b]pyridine (PhIP) etc could induce DNA DSB and cancer in both animal and human models [11], [12]. Thus, problems emerging from DSB repair pathways remain an important mechanism in cancer initiation and progression.

Oncogenes and cancer initiation

Most haematological and solid tumours are caused by either activation of certain genes that promote carcinogenesis (normally called oncogenes). Oncogenes are responsible for production of transcription factors, growth factors, receptors, genes involved with chromatin remodelling and apoptosis regulatory factors [4]. It is generally accepted that oncogenes are main cancer causing genes. Many studies done in mice model systems have explained the role of oncogenes in carcinogenesis and cancer progression and suppression. For example Jechlinger et al [13] cultured single cells extracted from the mammary gland of non-transgenic mice and examined the role of oncogenes in carcinogenesis and cancer suppression in primary cancer cells. This study found that mammary gland cells from the mice expressing doxycycline regulated Myc and [Kras.sup.G12D] (Oncogenes) lost their acini polarities (a feature of abnormally dividing cells at metaphase stage) and had increased cell proliferation rate; it was demonstrated that the cells filled up the lumen of the glands; suggesting loss of cell cycle control and increased cell proliferation. In addition, when the oncogenes were removed, the cells showed a significant reduction in cell proliferation --and the cells that earlier filled up the lumen underwent programmed cell death, with the exception of those at the tumour edge [13]. This study clearly demonstrates that oncogenes contribute much to carcinogenesis and tumour regression. Most importantly, the study also shows that cells at the edge of tumour may survive the effects of oncogene withdrawal by remaining in the state of dormancy till further events have occurred before another episode of growth can take place; this often contribute to tumour relapse (explained in detail below). However, the mechanistic events that switch the latent cells to cancerous progression still remain equivocal. These findings confirmed earlier reports of Adams et al [14] and Leder et al [15] that independently showed that mice carrying activated human tumour oncogenes developed cancer that resembles the human prototype. Thus oncogene-initiated carcinogenesis may be one mechanism for cancer development.

Tumour suppressors

Tumour suppressors are those molecules often involved in blocking tumour initiating signals. Several tumour suppressor genes have been investigated for a role in aetiology of cancer; for example loss--of--function mutation in a tumour suppressor gene NF1, which encodes Neurofibromin (a Ras GTPase-activating protein; RasGAP) has been reported as a cause of inherited cancer known as neurofibromatosis type 1 [16]. Neurofibromatosis type 1 has been associated with development of glioma [17]. It has been shown that NF1 is generated during cell cycle progression and degraded by Ras induced activation of protein kinase C (PKC); hence, inhibition of PKC resulted in accumulation and stabilization of NF1 in different human glioblastoma cells in vitro [17].

Also, it is widely known that retinoblastoma protein encoded by retinoblastoma gene is involved in cell cycle regulation in the retina. Meanwhile, a mutation in the tumour suppressor gene RB which is constitutively expressed in non-neoplastic cells has been associated with retinoblastoma--a childhood retinal cancer [18]. In fact, most recently, Xu et al [19] succinctly showed that maturing cone cell precursors with mutations in cancer suppressor gene RB1 contained a signalling network with oncogenic effects that resulted in retinoblastoma. Their works demonstrated that cone cells that lacked RB1 genes had a cell signalling network which suppressed normal cell death pathways and promoted cell survival. In addition, the proto oncogene Myc is known for its ability to mediate tumour suppressive responses including apoptosis. Murphy et al [20] and Kapproth et al [21] independently showed that deregulated expression of Myc was an early indicator of varieties of early stage cancer development. Furthermore, 73 % of null mice lacking the tumour suppressor myc and homologue of p53--TAP73, developed colon, intestine, liver and stomach cancer [22]. All these put together indicate that abnormalities affecting key tumour suppressor molecules may contribute towards development of cancer.

Epigenetic perturbations

More recently it has become clear that epigenetic alterations in the CpG islands near the promoter regions of tumour suppressor genes may also contribute to genetic instability. Many published studies have shown that epigenetic alterations at the loci that control different specific transcription factors may result in miss- interpretation of some histone codes and producing factors that can dysregulate cell cycle control machinery and cause cancer. For example, the carcinogenic potentials of the fusion of carboxyl terminal of Plant homeodomain (PHD) fingers (JARIDIA) with the transactivating domain of nucleoporin 98 (NUP98) to produce JARIDIA -NU98 has been studied [23]. This study found that cells transfected with JARDIA--NU98 fusion gene (a gene commonly seen in acute myeloid leukemia) proliferated indefinitely compared with the controls transfected with empty vectors. The study shows that chromosomal instability resulting from translocations may lead to production of factors that can disrupt methylation status or methylation -readout areas of some important loci in the DNA and cause cancer. Thus epigenetic perturbation may have some important implication in cancer initiation.

Dormancy and progression

Current reports indicate that even after formation of tumour that it remains in the state of dormancy marked by equilibrium between apoptosis and cell proliferation; the disruption of this state towards cell proliferation may eventually initiate tumour [24]. For this to occur, the cells must have acquired a number of mutations in key genes, normally this occurs over many years; this has been described as multistep carcinogenesis [5]. The multistep carcinogenesis is based on the Darwinian theory of evolution which explains the genetic changes that generates a new phenotype. It has been shown that the clonal proliferation of the parental cancer cell results in new population of cells selected for specific adaptive features often through sequences of heritable events, which determine their phenotype and behaviour--for example, a published study has shown that this process commonly results in generation of cancer cells with properties of growing to bigger size and increased invasiveness [25]. This phenomenon is often described as clonal expansion and forms important step in cancer development.

In addition, Chao et al [26] used a mathematical model system to illustrate how premalignant cells with mutation expand, which results in cells acquiring ability to fill the spaces left by normal cells that died through apoptosis; and how these events later allowed for development of a malignant phenotype through the process of clonal expansion. However, an important observation in that study was that environmental factors like ultraviolet -B caused a trigger to cell cycle dysregulation and cancer. Most recently, Klein et al [12] studied the fate of cell clones in mice subjected to radiation and examined how p53 mutation affected the behaviour of epidermal progenitor cells; the authors showed that there was a balance between the number of mutant cells that were lost and the mutants that proliferated after a brief exposure to the radiation--indicating a state of dormancy in the premalignant cell population. In that study, mice exposed to a brief UV-B radiation developed p53 mutant skin cells which did not result in skin cancer risk--suggesting that pre-malignancy was induced by short term exposure to mutagens, however, a continuous exposure of the mice to UV-B and sun light resulted in exponential increase in number of existing p53 mutant clones, this significantly increased the chance of developing skin cancer-- showing that time dependent accumulation of mutations may cause dormant or premalignant cells switched to malignant phenotype [12].

On the other hands, tumour dormancy can also be seen after successful treatment of cancer; in which case the cells maintain a balance between apoptosis and proliferation. However, this balance is often abolished in a time dependent fashion as the cells switch to progressive growth--marking an episode of cancer relapse. The exact mechanism underlying the process is not clear. It has been suggested that circulating tumour cells (CTC) which were shed over many years from a primary tumour could serve as a source of tumour relapse [27]. Meng et al [27] found that in 13 out of 36 patients whose breast cancer were treated till a dormant state was achieved, CTC cells were isolated after 7 to 22 years periods of breast cancer remission even with no evidence of clinically recognised disease; this indicates a high tendency of emerging from dormancy to malignancy. It is generally known that some breast and prostate cancer patients suffer and often die of cancer relapse years after tumour suppression during treatment. It is evident that CTC cells can establish a cross talk with the residual dormant cancer cells which could reprogram them for recurrence; however, the mechanism of this process still remains equivocal. Aguirre-Ghiso [28] suggested the existence of angiogenic, cellular and immuno-surveillance mechanisms as an underlying mechanism cancer dormancy and subsequent progression. It is clear that once cells emerged from state of dormancy and the tumour grows to a size that the available level of oxygen becomes insufficient for metabolism; some cells undergo apoptosis and regress while others are selected for adapting to such hypoxic environment; these cells acquire high potential of manipulating the angiogenic switch and other cellular markers to promote angiogenesis and metastatic behaviours. There are many volumes of published evidences showing that hypoxia and re-oxygenation are central to cancer progression.

Microenvironment and cancer progression

Most recently, Trimboli et al [29] showed that tumour microenvironment interacted with the constituent cells including stroma fibroblast, endothelial cells and epithelial cells to promote tumour growth and invasive progression of cancer. A micro dissection of tumour for global gene expression profile using microarrays identified 129 up-regulated and 21 down regulated genes within the tumour microenvironment [29]. A further studies in that report confirmed that 85% of the dysregulated genes were mainly responsible for malignant phenotypes of endothelial and epithelial cells [29]. The cross talk between these cells may be controlled by the redox status of the micro-environment. Published studies suggest that this communications within the surrounding environment controls angiogenesis, loss of cell cycle regulation and tumour behaviour [30]; [31]; [32]. There are sufficient number of evidences showing that hypoxic stress can induce genetic alterations and selects for cancer cells with aggressive genotypes and phenotype. The actual mechanism of this process remains poorly understood.

Self renewal, invasiveness and metastasis

There are evidences indicating that some cancer cells possess stem cell characteristics [8]. In fact, the contributions of cancer stem cells (CSC) in the growth and development of various forms of tumour including prostate and breast cancer have been widely recognized. Normal stem cells are defined by their ability to self- renew and differentiate into progeny. In normal prostate tissue, stem cells are the epithelial populations with full lineage potential to regenerate tissue specific progeny. In tumour, the contribution of cancer repopulating stem cells has been widely acknowledged; this cell clone have the ability to self renewal, repopulate tumour even during chemotherapy and may promote metastatic cancer progression [33].

Recently, Cicalese et al [33] compared pattern of cell division between CSC and normal stem cells; and showed that both symmetrical and asymmetrical cell divisions occurred in CSC while asymmetrical cell division was associated only with normal stem cells; asymmetrical cell division would result in production of progenitor cells while symmetrical cell division would give rise to two daughter cells which may be responsible for populating the tumour [33]. Cicalese et al [33] shows that tumour volume may be populated by CSC which possessed a decreased P53 activity; this may cause a shift from the usual asymmetric cell division to symmetric type and a resultant doubling of the cell number during cancer growth and development. Brabletz et al [34] has shown that the CSC accumulates mostly at the tumour edge and remains immobile initially until further transformation or remodeling by takes place. More evidence are available which strong provide support for the roles of CSC in aggressive tumour progression.

Epithelial mesenchymal transformation (EMT) is a process whereby epithelial cells lose their polarity and cell--cell junctions and acquire migratory characteristics [34]. Though this process is well recognised in normal early development in which it operates to enhance cell dissemination in vertebrate embryos, however, this process is greatly explored by cancer cells to migrate and spread to other organs or secondary sites. Furthermore, the concept that cancer cells which have undergone transformation from epithelial to mesenchymal phenotype, also acquire stem cell characteristics has also been proposed [34]. This hypothesis suggests that cancer cells residing in solid tumour may possess migratory stem-cell characteristics; and may retain such features after migrating to a secondary site [8]. The study of Brabletz et al [34] strongly supports this hypothesis. This study highlighted some peculiar molecular and cellular changes adopted by cancer cells including EMT controlled changes in other to metastasize to distant organ; for example transformation of stationary cancer stem cells (SCS-cells) often at the border of the tumour, makes the cells become mobile and more invasive and metastatic. From histopathology point of view, cells at the edge of sections are often associated with reduced extracellular matrix, allowing them to assume EMT-like feature. In clear terms, this study showed that cancer cells at the leading edge of invasive tumour may contain cancer cells with migratory tumour stem cells [34]. Many genes were suggested that may contribute to regulating this process including RUNX-2 and EMT controlled genes like TWIST, SNAIL etc. At this stage, the tumour has amplified the invasive signals from the constituent cells with subpopulations with progenitor behaviors or stem cell properties, thereby promoting cell proliferation, invasive potentials, metastatic phenotype etc. but how does this affect cancer cell movement of metastasis?

Emerging evidence from the work of Giampieri et al [35] clearly throws further lights on how cancer disseminate through lymph node or haematologous route is regulated. The authors showed that smad mediated transcriptional activation of transforming growth factor beta (TGF-[beta]) was associated with switching of tumour cells from cohesive movement to single cell- based motility and metastatic spread to secondary organs. In that study, tumour cells cultured in the presence of TGF- [beta] moved as single cells. Fast moving cells exhibited features suggestive of distant organ metastasis. When TGF-[beta] was knockdown, tumour cells grew as discrete colonies and moved cohesively; suggesting that TGF-[beta] signaling may be an early event in acquisition of metastatic properties especially in disrupting cell-cell interactive molecules and switching tumour cells from cohesive to single cell based motility through transcriptional activation of smad [35]. The study further showed that cells with TGF-[beta]--smad induced single-cell motility had increased intravasational movements (movements across the blood vessels); while cells with TGF-[beta] - smad knockdown had a cohesive or slow movement; this enhanced their ability to move to the local lymph nodes. The author also showed that TGF-B mediate aggressive cancer metastasis by inducing cell motility through the vascular route. It was suggested that smad mediated TGF-[beta] activation may be involved in organ specific dissemination of cancer, either through the haematologous route or through the lymph node at initial stage. Importantly, these molecules could serve as a potent drug target as a preventive measure of metastatic spread of cancer.

In conclusion, the current study has highlighted some of most recent understanding in the cancer initiation, malignant progression and metastasis. Though some important achievement have been made in understanding some important hit and lead molecules that cart cancer cells through various stages, It is recognized that more studies are required to further show in more detail the other molecular and signaling mechanisms underlying cancer initiation and progression. Therefore more work is still required to properly dissect the biology of cancer development. This would help in cataloguing preventive and therapeutic measures to control cancer development.

* Fund

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* Conflicts of interest;

* None


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Maxwell Omabe (1) * and Albert Egwu Okoroocha (2)

(1) School of Biomedical Science, Faculty of Health Science, Ebonyi State University Abakaliki Nigeria

(2) School of Biomedical Science University of Liverpool, UK

* Corresponding Author E-mail:
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Author:Omabe, Maxwell; Okoroocha, Albert Egwu
Publication:International Journal of Biotechnology & Biochemistry
Date:May 1, 2011
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