Molecular Biology of Cancer. Mechanisms, Targets, and Therapeutics. Lauren Pecorino. University of Greenwich. THIRD EDITION. 1. Cancer cells change mor- phologically, proliferate, invade other tissues, and metastasize. 18 The Molecular Biology of Cancer. The term cancer applies to a. The Rip-Tag model of islet cell tumor progression. Figure a The Metastatic cancer cells in bone marrow (Wright-Giemsa stain complex biological steps.

Molecular Biology Of Cancer Pdf

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Molecular Biology of Cancer. INTRODUCTION. SLIDE 1, 2 In the developed countries cardiovascular diseases are the leading causes of death. (34%), followed. PDF | Background Cancer is a genetic disease and mainly arises due to a number of reasons include activation of onco-genes, malfunction of. Departments of Radiation Oncology/Cancer Biology Section achieved in understanding the molecular basis of cancer. The accumulation of this basic.

Conversely, DNA hypomethylation may contribute to the activation of oncogenes, although the former occurs much more commonly. Inherited predisposition to cancer Whilst cancer as such is not inherited, there are a wide range of rare familial syndromes that predispose affected family members to cancer development.

We mentioned above cancer predisposition syndromes that are based on mutations in DNA repair enzyme systems Table 4, in The importance of DNA repair systems.

A by far larger number of familial cancer syndromes is based on mutations of tumour suppressor genes, of which a selection is shown in Table 2. It is interesting to note that germ line mutations of activated oncogenes are normally not inherited.

They may arise during gametogenesis, but the mutant alleles are typically dominant at the cellular level, which results in disturbance of normal embryonic development, and reduced viability of these embryos.

Fortunately, the inherited cancer predisposition syndromes listed in Tables 2 and 4 are extremely rare diseases, but they represent powerful illustrations for the importance of DNA repair and tumour suppressor genes for maintaining body homeostasis.

Principal applications of genetic testing in cancer As an increasing number of cancer-related genes or gene mutations is characterised, the potential of DNA and RNA expression testing for cancer-related applications is being explored. Principal applications include: Gene mutation screening in families with inherited cancer predisposition syndromes, which identifies at- risk individuals in such families and allows for decisions to be made about early disease monitoring, aggressive treatment regimens and prophylactic surgery e.

Gene expression microarray analysis can be used for classification of cancer subtypes, e. Other applications include the diagnosis of benign vs.

Tumour cells may be recognised by the immune system through the expression of tumour-associated antigens, but the antigenicity varies considerably between different types of antigens. In order to avoid an attack by the immune system, tumour cells use a range of strategies, such as suppression of expression of tumour-associated antigens or of MHC class 1 molecules, or even counterattack against immune cells.

Research into immunotherapy of cancers aims to devise novel strategies to support the anti-cancer immune response; principal approaches include: Antigen-independent cytokine therapy e.

Herceptin, Rituxan. Novel approaches arising from cancer cell biology The progress in our knowledge about gene mutations frequently occurring in cancers, combined with the development of modern molecular biology methods has led to both new diagnostic tools see Principal applications of genetic testing in cancer and new treatment modalities that have shown some success in the management of selected types of cancers.

The knowledge about cancer—associated genes and their role in cellular growth signalling pathways has led to the development of a considerable number of anti-cancer drugs targeting such signalling pathways: 1 monoclonal antibodies that target the extracellular domains of growth factor receptors and 2 small-molecule inhibitors, targeting either receptor tyrosine kinases or other components of growth signalling pathways, such as Ras, b-Raf or mTOR Figure.

Two examples of such successful anti-cancer agents are the monoclonal antibody Herceptin for the treatment of a specific subtype of breast cancer, and the small-molecule inhibitor Gleevec targeting the fusion protein Bcr-abl, a mutant tyrosine kinase, involved in the development of chronic myeloic leukaemia CML. A third group of potential drug targets are some anti-apoptotic proteins that are frequently overexpressed in cancer cells.

Figure 6. Targets of novel anti-cancer drugs in cellular growth signalling pathways.

The cell membrane is indicated in light grey, red diamonds represent growth factors, green shows the growth factor receptor with the intracellular tyrosine kinase domain Tk indicated by the red circle.

Dotted black arrows point to cell biological outcomes of these pathways. Groups of novel anticancer drugs and their targets are shown in red.

The biology of cancer. Additional capabilities crucial to cancer phenotypes that are not shown here include defects in DNA repair mechanisms and signalling interactions of the tumour microenvironment. Hallmarks of cancer: the next generation.

Cell, [7] Self-sufficiency in growth signals: Tumours have the capacity to proliferate without external stimuli, usually as a consequence of oncogene activation. Insensitivity to growth-inhibitory signals: Tumour cells may not respond to molecules that are inhibitory to the proliferation of normal cells.

Molecular Biology of Human Cancers

Evasion of apoptosis: Tumours may be resistant to programmed cell death, as a consequence of inactivation of p53 or overexpression of anti-apoptotic proteins. Limitless replicative potential: Tumour cells have unrestricted proliferative capacity, associated with maintenance of telomere length and function. Sustained angiogenesis: Tumours are not able to grow without formation of a vascular supply, which is induced by various factors, the most important being vascular endothelial growth factor VEGF.

Ability to invade and metastasise: Tumour metastases are the cause of the vast majority of cancer deaths and depend on processes that are intrinsic to the cell or are initiated by signals from the tissue microenvironment. Back to top Further reading Chapter Molecular biology of the cell, 5th edition.

Hanahan D, Weinberg RA. Karp G. Chapter In: Karp G.

Cell and molecular biology: concepts and experiments, 6th edition. Stricker TP, Kumar V. Chapter 7.

Introduction to the Cellular and Molecular Biology of Cancer

Robbins and Cotran pathologic basis of disease, 8th ed. Weinberg RA.

The biology of cancer, 2nd ed. In the field of stem cell research, genetic analysis of human embryonic stem cell hESC lines, a pluripotent cell type that shares numerous characteristics with cancer cells, has also revealed multiple CNVs, and few of them are also recurrent, including losses of chromosomal band 18q21qter, and whole or partial gains of chromosomes 1, 12, 17 and 20 34 , Notably, 20q Previously, BCL2 like 1 BCL2L1 , which is located in the smallest common chromosomal region of gain and regulates the mitochondrial apoptotic pathway, has been confirmed as the key-driver gene of this amplification 37 , Accordingly, the overexpression of Bcl-xL, an anti-apoptotic isoform of BCL2L1 has offered cells a survival advantage by preventing apoptosis 37 , Overexpression of this gene may also be responsible for the gain of 20q in various human cancer types DCC, located in the chromosome band 18q However, much of the reported data on the loss and inactivation of DCC is circumstantial and fails to provide conclusive evidence that DCC functions as a tumor-suppressor gene Furthermore, to the best of our knowledge, there is no evidence that germline mutations of DCC serve a role in heritable cancer; and few somatic mutations in DCC have been reported in CRC TP53 TP53 is a tumor-suppressor gene located on the short arm of chromosome 17, which is commonly lost in colorectal carcinoma Upon DNA damage, for example, TP53 induces cell cycle arrest at the G1 or G2 phase, or triggers apoptosis when the damage is too severe and irreparable TP53 alteration is the hallmark of human tumors, and the status of TP53 mutation is associated with the progression and outcome of sporadic CRC Liu and Bodmer 69 have analyzed TP53 mutations and their expression in 56 CRC cell lines, and reported a relatively high frequency of TP53 mutations These mutations render an inactive protein with an abnormally long half-life that is detectable by immunohistochemistry The high frequency of KRAS mutations and its appearance at a relatively early stage in tumor progression suggest a causative role of KRAS in human tumorigenesis.

Several studies have reported an association between KRAS mutations, and poor prognosis of CRC 77 , 78 , and lung 79 , 80 and liver 81 metastasis. In contrast, several other studies reported that KRAS mutations were strong independent predictors of survival in patients with CRC 80 — These contradictory findings may be explained by the differences in the distribution of specific KRAS mutations, stage at diagnosis or other characteristics.

KRAS mutations have emerged as an important predictive marker of resistance to anti-epidermal growth factor receptors EGFR agents, including panitumumab and cetuximab 83 — The most frequent changes observed in these codons are the substitution of glycine for aspartate p.

G12D, p. G13D G12V mutations Microsatellites are repetitive DNA sequences consisting of tandem repeats, usually between one to five base pairs. Patients with MSI phenotype exhibit a high frequency of replication errors, particularly in repetitive DNA sequences, primarily due to the slippage of the DNA polymerase Tumors are then classified based on the number of microsatellites exhibiting instability.

Impairment of MMR genes can occur by either mutational inactivation or by epigenetic inactivation through CpG island methylation of the promoter of the genes.

Loss or insufficiency of MMR activity leads to replication errors with an increased mutation rate and a higher potential for malignancy. These alterations in the gene functions represent a possible mechanism for MSI carcinogenesis.

The Molecular Biology of Cancer

CIMP or aberrant DNA methylation Transcription inactivation by DNA hypermethylation at promoter CpG islands of tumor-suppressor genes, causing gene silencing, is now recognized as an important mechanism in human carcinogenesis — Overview of the genetic and epigenetic instability pathways that drive colorectal cancer onset and development.

Clinical implication of the molecular genetics of CRC The prognosis and therapeutic options for patients with CRC are associated with the stage at which they are first diagnosed.

While early stage CRC is often cured with surgery alone, more advanced or metastatic CRC generally require additional adjuvant chemotherapy or targeted therapy, either alone or as a combined treatment. Early detection of CRC thus becomes important to reduce the incidence and mortality of the disease.

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Thus, identifying molecular prognostic markers that are capable of recognizing patients with CRC more likely to recur or benefit from adjuvant chemotherapy may improve the prognosis and assist in the selection of appropriate therapy, and subsequently the general outcomes. It is now widely known that certain alterations at the molecular level favor CRC onset, progression and metastasis Patients with inactive TP53 mutations, for example, are at an increased risk of mortality compared with their counterparts, but this mutation does not appear to affect the outcome of chemotherapy Thus, KRAS mutation status is currently used in clinical settings to predict the therapeutic effectiveness of CRC prior to chemotherapy to avoid any undesired effects and medical costs APC is another commonly affected gene whose mutations generally appear in the early stage of CRC development 55 , However, its predictive role for the response to chemotherapeutic agents, including 5-fluorouracil 5-FU is conflicting.

Several studies demonstrated a lack of benefit of 5-FU-based adjuvant chemotherapy in patients with CRC with MSI tumors — , while others reported the beneficial effects , Des Guetz et al performed a meta-analysis involving 3, patients from seven different studies, and reported that chemotherapy had a beneficial effect among MSS, but not MSI-H patients In addition, the more improved survival rate of MSI-H patients was due to a better prognosis rather than the benefit of chemotherapy These findings suggested that MSI may be considered as a predictive marker of chemoresistance and that patients with CRC with MSI may be spared from adjuvant treatment.

Several groups have used gene expression profiling to classify CRC, and to identify genes associated with prognosis and prediction of disease outcome.Cancer Pathways. These alterations in the gene functions represent a possible mechanism for MSI carcinogenesis. However, much of the reported data on the loss and inactivation of DCC is circumstantial and fails to provide conclusive evidence that DCC functions as a tumor-suppressor gene The development of therapies specifically targeting the molecules responsible for the transformed phenotype demands a detailed understanding of the mechanisms behind normal cellular processes.

Several groups have used gene expression profiling to classify CRC, and to identify genes associated with prognosis and prediction of disease outcome. Note that clinical staging typically refers to the later observations and cannot be correlated with the genetic events.

As a result, it has become clear that the morphologies of the cancers depend on the kind of the abnormal gene.