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Cancer is a tremendously complex, heterogeneous disease which displays degree of intricacy at the physiological, tissue and cellular level. Cancer cells are usually characterized by indefinite cell proliferation, malformed patterns of differentiation processes and reduced ability to induce apoptosis and genetic instability. The recent focus of cancer research has been the interaction between the tumour and the microenvironment it surrounds as the bidirectional interaction is a prominent factor for growth, survival and the formation of distant metastasis (Alberti 2006). However, the molecular mechanisms that underlie interaction between cancer and their microenvironments are unclear. A tumour usually contains several different pathological cancer subtypes, which is known as tumour or cancer tissue complexity. This level of complexity is known to provide functional redundancy for cancer tissue to uphold cellular heterogeneity, which can direct to tumour recurrence (Harris et al., 1982, Ling et al., 1984, Chambers et al., 1984). This also depends on the survival of fraction of metastatic potential cancer cells after the treatment of anticancer. Cancer has the potential of recovering from the anticancer treatment as the one cancer subtype is highly functionally able to replace another subtype or even multiple subtypes (Bissell and Radisky 2001, Petersen et al., 2001). This allows the cancer to grow, survive and recur (Wang et al., 2007). The cancer cell itself controls the growth andÂ metastasesÂ of the tumour through the tumour stroma and the systemic influences. This is due to the interaction between growth factors and the growth factors receptors on theÂ cell surface membrane (Vokes & Chu, 2006) which thereby results in the chain of enzymatic reactions that initiates the dual signal transduction which then facilitates the reproductionÂ and inhibition of programmed cell death (apoptosis) of the cancer cell (Faivre et al., 2006, Gollob et al., 2006). The production of growth factors in the tumour cells can be under autocrine, paracrine or endocrine mechanisms (Henke et al., 2006;Â Kumasheva & Houghton, 2006, Yashwanth et al., 2006, Balducci 2007).
The development of cancer relies on the acquirement and selection of specific features that distinctly apart the somatic cells from the tumour cells. It is thought that the majority of tumours originate by initial mutations in normal somatic cells, a pathway that might be stimulated due to cell's inherent genomic instability (Lengauer and Kinzler 1998). However, it remains unknown at to which extent genomic instability plays its part in the initiation of cancer development. It is known that the cancer is a result of accumulation of many mutations that irreversibly transfers the somatic cells into a tumour cell. These mutations occur over time and results in the disruption of normal processes such as growth, proliferation and death which in turn leads to accumulation of many cancerous cells thereby forming tumour mass. Moreover, cancer cells have to acquire mechanisms to divide infinitely and become immortalised which is directly related to the telomeres sequences at the end of chromosomes. In normal cells, these sequences gets shorter and shorter as the cells divides but in the case of tumour cells this shortening problems is avoided via the activation of telomere enzyme telomerase that keeps adding the telomeres thereby enabling the cancer cells to proliferate indefinitely (Knudson 2002, Bártová et al., 2009).
Genetic Damage in Cancer Cells
The phenotypic description of cancer involves the infinite replication potential, avoiding apoptosis, tissue invasion, self-reliance in growth signals and unrelenting angiogenesis (Hanahan and Weinberg 2000). These characteristics originate due to the accumulation of genetic and epigenetic abnormalities which thereby leads to dysregulation of normal regulatory cellular processes. Recent research and advances in this field have enabled in depth analysis of these abnormalities, directing towards improved understanding of malignant transformation and the discovery of new therapeutic targets. The prominent distinction between normal and tumour cells at the cytological level are the changes in nuclear shape, nucleoplasmic texture and number of nucleoli (Lanctot et al., 2007, Zaidi et al., 2007, Zink et al., 2004 True et al., 2004). However, the meaning of these changes at the cytological level for the cancer phenotype is unclear (Lever and Sheer 2010). The accumulation of genetic mutations in cells partly activates the tumour development and progression. In cancerous cells, many forms of gene alterations, such as gene sequence mutations (Lievre et al., 2006, Blons et al., 2006) gene and chromosomal fragment augmentations, fusion of genes and translocation of chromosomes (Tsafrir et al., 2006, Hughes et al., 2006, Taki and Taniwaki 2006, Zhang et al. 2006) gene deletions (Gallegos-Arreola et al., 2003, Cesar, et al., 2004) and even the dysregulations and mutations of non-coding RNAs, such as microRNAs (Iorio et al., 2005, Calin and Croce 2006, Volinia, et al., 2006), have been researched and recognized widely. A recent genome-wide screening of cancer mutation genes demonstrated that even clinical samples of same cancer subtype had varied set of genetic mutations with different functions indicating that they belong to different pathways and thereby implied that the cancer can develop via multiple genetic routes (Wang et al., 2007, Sjoblom et al., 2006).
Epigenetics involves heritable modifications in the biochemical and structural state of chromatin, which does not affect the sequences of DNA; hence, modifications in the nuclear radial arrangement of chromosomes can also be classified as epigenetic events (Bártová et al., 2009).
Nuclear organisation of tumour cells
Aneuploidy and rearrangement of chromosome are linked functionally to the tumour development together with the specific changes in the non-random chromosome organization within the intrephase nuclei. Likewise, heterogeneity in the copy number of individual genetic loci has been demonstrated in cancer cells. Not surprisingly, the changes that originate in the nuclei of the cancer cells tend to involve chromatin-related domains which are responsible for the regulation and control of the tumour-associated gene expression. The mutual intermingling between chromosome territories (CTs) enables close interaction between two neighbouring CTs. However, the physical interaction between two neighbouring CTs is what enhances the probability of chromosomal translocations, which are frequently discovered in cancer cells. The scientific researchers have used various CT interphase distribution models to describe the rules of nuclear arrangement. Despite the differences in the models of the CT interphase, it is apparent that the cancer cells are characterized by specific nuclear arrangements of cancer-related genes. Generally, the rate of exchange abnormalities for a particular chromosome is more or less proportional to its total DNA content. However, according to the linear proportionality model, higher than expected rate of interchanges have been calculated for numerous chromosomes implicated in cancer-related translocations, particularly evident in certain kinds of leukaemia. Thus, present understanding of the functional significance of chromatin structure implicates the positioning of nuclear gene as a promising diagnostic tool for cancer therapeutics.
In comparison to other cancer-suppressor genes and proto-oncogenes, the c-myc proto-oncogene is a very inscrutable prognostic marker of cancer progression. This proto-oncogene can be triggered by gene amplification, pro-viral insertion, retro-viral transduction and chromosomal translocation. The function of c-myc includes the responsibility of cell-cycle progression and activation of differentiation processes. The literature suggests that the over-expression of proto-oncogene c-myc seen in several tumour cells is due to more other factors contributing rather than solely due to c-myc karyotype instability, which does undoubtedly plays a significant role in early tumourigenesis. The regulation of the c-myc gene expression is carried out by the APC gene which is activated through the ï¢-catenin signalling pathway. Thus it is been put forward that either the mutation in the APC gene or activating ï¢-catenin leads to the over-expression of the c-myc gene in colorectal cancers (Bártová et al., 2009).
Epigenetics of tumour cells
The functional relationship between gene expression and structure of nucleus in neoplastic cells is consistent with the detection of epigenetic changes in the tumour-related genes. The epigenetic changes that originate specifically in the cancerous cells have the potential to be reversed with the use of anti-cancer therapies, unlike the aneuploidy and chromosome translocation which are irreversible modifications (Bártová et al., 2009). The first epigenetic modification to be discovered in tumour cells was the genomic DNA hypomethylation; this global DNA modification is down to an absence of methylation in repetitive sequences in the genome, event that is linked to the chromosomal instability which leads to tumourigenesis. Other more frequent modified epigenetic markers of human tumour cells are histone methylation and histone acetylation. This modification process of histone is a complex process and it is responsible for regulating the nuclear processes. Thus, the abnormalities in the nuclear processes are linked with the tumour formation (Bártová et al., 2009). These epigenetic modifications can collaborate with genetic modification to cause the evolution of a tumour because they are mitotically heritable (Jones and Baylin 2007). Distinctive epigenetic patterns are also reported in the tumour-suppressor genes and proto-oncogenes of neoplastic cells. However, increased DNA methylation is frequently observed in tumour-suppressor genes of neoplastic cells which also play role in the development, survival and proliferation of tumour cells (Bártová et al., 2009).
Other tumour-associated genetic mutations
Mutations in oncogenes and tumour suppressor genes are frequently reported in cancers and these modifications are highly significant in the pathogenesis of cancers. Thus, such mutational changes can be acknowledged as a marker for tumour-derived DNA. The study by SorensonÂ et alÂ in 1994 reported KRASÂ gene mutations in the plasma and tumours of three pancreatic cancer patients. This study results provided direct evidence for the existence of tumour-derived DNA in the circulation of these cancer patients. Moreover, recent studies have also documented that the tumour-associated genetic mutations can be found in the plasma of individuals been exposed to carcinogens, and the existence of such genetic mutations in the circulation may indicate high risk of tumourigenesis (GormallyÂ et al, 2006;Â HagiwaraÂ et al, 2006) (Chan and Lo 2007).
The mutations and other genetic alteration in the protein-tyrosine kinases (PTKs) signalling pathway, which are key regulators of intracellular signal-transduction processes, can result in the dysregulated kinase activity and transformation into malignant form (Blume-Jensen and Hunter 2001). Other signalling pathways such as the Wnt and Hedgehog (Hh) signalling pathways were recently reported to be implicated in the postembryonic regulation of stem-cell number in epithelia. Recent studies have reported that the mutations in the pathway, which are frequently associated with specific human cancers, leads to the activation in transcriptional response of these pathways. This tumour formation process associated with pathway activation may be down to misspecification of cells towards stem-cell or stem cell-like fates (Taipale and Beachy 2001).
Cancer continues to be the leading cause of death in developed countries even with the advances in anticancer therapies. In the treatment process, the severity of disease at the diagnostic level is a significant factor for determining treatment outcome. Accordingly, with the aim of screening malignancies at early stage, tumour markers have been developed. In addition, these markers are also useful in population screening, diagnosis, staging, or following up the progression of cancer as well as its prognostication (Chan and Lo 2007). The most common tumour markers are tumour-associated proteins, presenting a reputed clinical use in cancer. The detection of tumour can be carried out in a solid tumour, circulating tumour cells in periphery, bone marrow, lymph nodes, or in other bodily fluids (Lindblom and Liljegren 2000). An example of specific tumour marker which is solitarily expressed only in cancer cells is the so-called fusion proteins. These cancer-associated proteins are coupled with the malignant processes in which an oncogene is translocated and fused to another gene's active promoter. Thus, the outcome is the consistent active production of the fusion proteins, which then leads to the development of malignant duplicate. The best known example is the Philadelphia chromosome in chronic myeloid leukaemia (Melo 1996, Lindblom and Liljegren 2000).
The other not so specific tumour-associated marker is oncofetal antigens, which have the cellular expression during the embryological development and in tumour cells. Most frequently used oncofetal antigen, which is highly expressed in all the gastrointestinal tumours and also in many other tumours is the so-called carcinoembryonic antigen (Hunerbein 1998, Lindblom and Liljegren 2000). Other well known protein antigens are the cancer/testis (CT) antigens which are capable of inducing an immune response in cancer patients, with highly tissue-restricted expression in adult testicular germ cells and are being tagged as promising target molecules for tumour vaccines. These protein antigens are abnormally active and expressed in various proportions in many types of human malignancies. At present, more than 100 CT antigen genes have been documented in the literature (Caballero and Chen 2009).
Cancer Testis Antigens
The most promising tumour-specific antigens are the ones that belong to the family of CT antigens. Natural humoral and cellular immunogenicity against CT antigens can regularly be seen in individuals with cancer. The first ever CT antigen to be documented was melanoma antigen 1 (MAGE-A1), which was recognized as a target for autologous T-cells in individuals with melanoma cancer. Afterwards, the family of CT antigens has grown to just less than 200 members. The family of CT antigens seems to divide into two categories based on their chromosome localization, one being the chromosome X-encoded CT antigens (highly expressed in germ cells until the spermatocyte stage of spermatogenesis) and other being the CT antigens which are mainly encoded by autosomal single-copy genes (higly expressed in spermatocytes and later stages of spermatogenesis). Some of the known antigens included in first category are the MAGE, GAGE, NY-ESO-1 antigens whereas in the second category are the ADAM2, BRDT, MORC, TPTE antigens (Gjerstorff et al., 2010).
CT antigen expression in normal tissues
The CT antigens expression is dominating in the different tissues during foetal development. However, their expression dominates in the sites of immunological tolerance after birth. In both germ and cancer cells CT antigens seem to be having coordinated-fashioned expression but there are examples of coordinated-fashioned expression of antigen in nongermline cells during foetal development. In a recent genome-wide expression survey showed that the many CT antigen genes were expressed in nontesticular tissues and were consequently then recategorized either as the testis-restricted, testis-selective or testis-brain-restricted. This study also revealed that broadly the expression of chromosome-X-encoded CT antigens is highly restricted in comparison to autosomally-encoded CT antigens (Gjerstorff et al., 2010).
CT antigen expression in human cancers
As mentioned above, the expression of CT antigens in wide range of human cancers of different histological origins, are quite variable in proportions but frequently being the highest among the melanoma and lung, breast, esophagus, bladder, ovary, head & neck carcinoma patients. In contrast to this, the antigen expression is only hardly ever seen in individuals with leukemia, renal, colon, kidney or gastric carcinomas. In literature, many studies have documented a strong association between cancer progression and expression of CT antigens. Moreover, some CT antigens have also been coupled with poor prognosis implying the antigen role in tumour progression (Gjerstorff et al., 2010).
Function of CT antigens
The functions of CT antigens in both normal and cancer cells are unclear. Specifically, the reason for their expression in cancer cells is not known as the expression can be due to either them contributing towards the development of tumour or merely it's due to the epigenomic and genomic instability. Recent data suggested that the CT antigen family members "MAGE-A group" are implicated in regulation of apoptosis (programmed cell death), tumour cell cell-cycle progression via the direct protein-protein interactions and control of gene expression. They also have influence on the cancer growth and invasion. Whereas, the CT family members belonging to the autosomally-encoded CT antigens group are seems to be implicated in more specific mechanisms of spermatogenesis. The limited data on the functions of CT antigens due in fact implicate the antigens in contributing to the tumurogenesis but more research is needed to clarify their role (Gjerstorff et al., 2010, Ghafouri-Fard and Modarressi 2009).
Cancer diagnosis using CTAs
Intraphepatic cholagiocarcinom (IHCC): IHCC is a relatively rare cancer, encompassing around 5%-10% of the liver cancers. A recent study investigating the expression of CT antigens in IHCC to evaluate their potential therapeutic values tested 89 IHCC patients using the antibodies against the CT antigens. The study showed the positive MAGE-3/4 expression correlated with larger tumour size, tumour relapse and poor prognosis. In addition, the study results showed that the 52 IHCC cases with a minimum one CT antigen marker expression group displayed a higher frequency of larger tumour sizes and quite short survival rates in comparison to other cases. In summary, the data clearly suggested that the specific immunotherapy targeting the CT antigens might well be a novel treatment option for patients with IHCC (Zhou et al., 2011).
Gastrointestinal stromal tumor (GIST): A recent study confirmed the CT antigen expression in GIST and the antigen role as marker for prognosis. The study included 35 GIST patients being tested for the expression patterns and prognostic roles of CT antigens. 49% GIST patients with tumour that positively expressed CT antigen had a significantly shorter recurrence free survival in comparison to the cases with negative CT antigen expression. Specifically, the expression of MAGE-A3 and NY-ESO-1 were clearly linked with tumour progression under imatinib treatment. Furthermore, a worst tumour response to imatinub was seen in the positive-CT antigen tumours. To summarise, the study results showed the important role of CT antigens expression in the GIST patients with the potential impact of antigens on the tumour response to imatinib. However, further studies are required to confirm the present results (Perez et al., 2011).
Hepatocellular carcinoma (HCC): HCC is highly heterogeneous as it involves the various pathological entities and intricate range of gene modifications that has its effects on the supramolecular processes. Studies investigating the expression of CT antigens in the HCC patients showed that there were number of CT antigens which were highly expressed in HCC. Thus these antigens clearly have the potential for being the promising targets for antigen-specific immunotherapy. A study by Zhao et al group investigated the expression by testing the 105 HCC tissues for the MAGE1, SSX- 1, CTp11 and HCA587 mRNA expression. The results of the study clearly stated the high expression for the tested antigens mRNAs in the HCC-positive tissues. This study suggested applying the CT antigen mRNAs as tumour-specific markers to detect HCC cells in circulation might well be an adjuvant diagnostic tool (Grizzi et al., 2007).
The aspect of cancer treatment has considerably transformed over the last hundred years. The era of surgery and tumour being only hope for the treatment of tumours has finally ended. Here we will discuss the recent and emerging approaches to the treatment of malignancies. There are number of novel drugs are in pipeline awaiting clinical development and for the time being novel strategies for instance the anti-angiogenic approach and viro-therapy are making their way to the clinical settings. Recent focus on the new biomarkers as promising targets in treatment of cancer has been astonishing. Other more recent emerging novel therapies include the cancer immunotherapy. The immunotherapy is aimed at inducing the effective targeted immune response against tumour cells. There are some non-specific types of immunotherapy for example the interferon alfa and interleukin 2 which are aimed at inducing generalized immunogenicity against tumour cells. Finally, the therapeutic cancer vaccines are being developed which will accomplish two goals - first, it will stimulate exact immune responses against the selected target and second the immune responses will be adequate enough to surmount immunosuppressive mechanisms employed by tumours (Bilusic and Madan 2011).
Many anti-cancer immunotherapies have been developed and investigated in array of clinical settings and a lot of them have involved CT antigen targets. MAGE-A antigens stays the attractive therapeutic targets, as they demonstrate general expression profiles among tumours and are linked with the tumour progression and poor prognosis. The first study which used MAGE-A3 vaccination involved metastatic melanoma patients. The study showed tumour regression in 3 of 6 cases after subcutaneous injections of MAGE-A3 peptide without adjuvant. Other larger study subsequently confirmed the results. These studies presented researchers with the proof of evidence that the MAGE-A3 peptide vaccination in fact can be an effective strategy for treatment of cancer. Several studies have been conducted with MAGE-A protein antigens attempting to enhance antigens' immunogenicity using viral-carriers and protein fusions. However, the results obtained from most of these studies remains to be determined. The CT vaccine utmost in development is the MAGE-A3 vaccine of GlaxoSmithKline at present under Phase 3 assessment for Non-small cell lung cancerÂ (NSCLC). This vaccine comprises of MAGE-A3-influenzae protein D fusion formed inÂ Escherichia coliÂ and adjuvant AS02B. The MAGE-A3 vaccine is also being assessed for treatment in other malignancies. NY-ESO-1 is also at present being investigated in number of clinical studies. A study showed the effect of NY-ESO-1 with the saponin-based adjuvant ISCOMATRIX (CSL Behring) vaccine in patients with melanoma. The vaccine induced the high-titer antibody responses and circulating CD4+Â and CD8+Â T-cells with specificity for a broad array of NY-ESO-1 epitopes.
In addition, individuals receiving the vaccine showed longer recurrence-free survival rate in comparison to controls in the study. In contrast, vaccine seemed to had no effect on the patients with advanced metastatic melanoma. These patients showed diminished levels of T-cell-responsiveness and elevated frequency of circulating-regulatory-T-cells (Tregs), in comparison to the patients with the minimal residual disease, thereby implying that during the melanoma progression the immune suppression develops. However, the studies investigating efficacy of the NY-ESO-1/ISCOMATRIX vaccine for the treatment of melanoma are in progress. The Cancer Vaccine Collaborative (CVC), a partnership between the Cancer Research Institute and the Ludwig Institute for Cancer Research, symbolises a new academic model for developing, coordinating, performing and monitoring cancer vaccine trial. The initial CVC vaccine trail will include the NY-ESO-1, a prototype cancer-testis (CT) antigen which have demonstrated strong spontaneous humoral and cellular immunogenicity (Old 2008).
Dendritic Cell Vaccines
Numerous clinical trials investigating dendritic cell (DC)-based vaccinations using autologous DC and tumour-associated antigens have been carried out to evaluate the efficacy of these vaccines to induce clinical responses in cancer patients. Various Phase 3 clinical trials of DC-based vaccinations for asymptomatic metastatic hormone-refractory prostateÂ cancer (HRPC) patients carried out by the Dendrion Corporation (USA) showed considerably longer overall survival in treated patients in comparison to patients receiving the placebo. Together, these results suggested that the DC-based vaccination could be a promising treatment option for many cancers, but several obstacles must be overcome before the development of an inexpensive DC-based vaccination that can be used worldwide (Itoh et al., 2009).
Cancer is indeed a somatic heterogeneous disease which involves the modification at cellular, molecular, immunological and genetic level. Therefore the therapies treating the cancer require to act in all aspects to provide the effective treatment against the progression, disease relapse and metastasis. The recent emerging novel therapies and diagnostic tools are the CT antigens (a diagnostic tool for early detection and thereby improving the prognosis), cancer immunotherapy including the tumour-associated antigens and cancer vaccines which includes the dendritic cell vaccines and other vaccines. Many of these CT antigens have been proven to be immunogenic against number of tumours. However, the questions that still needs answering are the exact biological function of CT antigens products in normal and cancerous cells and also their higher expression in the tumour cells. Due to these emerging immunological-based cancer therapies there is much hope for the improvement and effectiveness in the future treatment of cancers.