Brief overview of cancer cells.pdf

CANCER CELLS a brief overview of introductory cancer biology OUTLINE Cancer Cells      General Principles of Tumour Biology Introduction to Cancer Biology Types of growth disorder Definitions of and distinctions between different types of growth disorder Hallmarks of Cancer reading the re...

CANCER CELLS a brief overview of introductory cancer biology OUTLINE Cancer Cells      General Principles of Tumour Biology Introduction to Cancer Biology Types of growth disorder Definitions of and distinctions between different types of growth disorder Hallmarks of Cancer reading the recommended texts are:  The Biology of Cancer by Robert Weinberg (Garland Publishers ) – 2nd ed - Garland Science, New York, NY (2014) Other useful books       Cancer Biology (2000; 2nd ed) by RJB King (Prentice Hall Publishers) DeVita: Devita, Hellman and Rosenberg's Cancer: Principles and Practice of Oncology, 8th ed., 2008 Hong: Holland-Frei Cancer Medicine, 8th ed., 2010 Pitot, H.C., Fundamentals of Oncology, 4th ed, Marcel Dekker: New York and Basel, 2002 Ruddon, R.W., Cancer Biology, 4th ed, Oxford University Press: Oxford and New York, 2007 Plus reviews / articles Cells are the fundamental working units of structure and function Cells are the fundamental units of disease Cell response to stress  Cell adaptation  Reversible cell injury  Irreversible cell injury Causes of cell injury  Hypoxia  Physical agents  Chemical agents  Infectious agents  Immunologic  Genetic  Nutritional Cellular response to stress. The normal cell can respond to stress in two ways. Cellular adaptation     A normal response to an appropriate stimulus. Permits survival and maintenance of cell function. May enable a cell to change size or form. Abnormal cellular changes may also occur. Cellular growth involves two fundamental processes: 1. Growth in cell size. 2. Growth in cell structure and function called differentiation.  The adaptive changes in cell growth, size and differentiation underlie many pathologic processes. Cellular adaptation  Cells must constantly adapt (adjust), even under normal conditions, to the changes in their environment due to increased work demand or threats.  These adaptations may be physiological or pathological. Physiological adaptations usually represent responses of cells to normal stimulation by 1hormones, 2endogenous chemical substances or 3exogenous factors.   Pathologic adaptations may share the same underlying mechanisms as physiological adaptations but they provide the cells with the ability to survive in their environment and perhaps escape injury. Cellular growth disorder and adaptation  1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. Forms of cellular adaptation and growth abnormalities Hypertrophy Hyperplasia Aplasia Malformation Ectopia Atrophy Metaplasia Dysplasia Neoplasia Anaplasia Desmoplasia Invasion Metastasis … Metaplasia  Metaplasia is a change of the histological type of tissue within the same germ cell layer i.e. changes of one type of epithelium to another type of epithelium or one type of connective tissue to another type of connective tissue. Metaplasia of normal columnar (left) to squamous epithelium (right) in a bronchus shown schematically (A) and histologically (B). Metaplasia        One cell type is replaced by another. Cells that are normally columnar or stratified may change to squamous. May predispose to cancer. Involves reprogramming of undifferentiated stem cells. Allows cells to better survive in a hostile environment. Is reversible. Is a response to chronic irritation and inflammation. Metaplasia  Examples of metaplasia  With continued smoke exposure, ciliated columnar cells are changed to stratified squamous cells.  Cervical cells change when exposed to human papillomaviruses (HPV) Continued exposure may predispose to cancerous transformations.  Dysplasia   Dysplasia means disorderly growth. Deranged cell growth resulting in cells of varying size, shape and appearance.  Dysplasia is a pre-cancerous (pre-malignant) change. It is therefore important to recognise dysplasia in the tissue.  The most common site of dysplasia is the cervix. Other sites include stomach and urinary bladder.  Dysplasia   May be associated with chronic irritation or inflammation. May be reversible if offending agent is removed.  Dysplasia is considered a strong precursor of cancer! e.g. cervical dysplasia.  However, dysplasia is an adaptive process may or may not lead to cancer. Decrease risk if irritation is removed or inflammation treated.  Neoplasia abnormal cell growth  Neoplasia is a mass of tissue formed as a result of abnormal, excessive, uncoordinated, autonomous and purposeless proliferation of cells even after cessation of stimuli for growth which evoked or caused it.  Majority of neoplasms can be categorised clinically and morphologically into benign and malignant on the basis of certain characteristics. benign and malignant tumours Characteristics Benign tumours Malignant tumours Growth type Expansive Infiltrating Growth speed Slow (in general) Rapid (in general) Structure Typical Atypical Mitoses Rare – typical Low mitotic count, normal mitosis Numerous – atypical Low to high mitotic count, abnormal mitosis Invasion No (often compresses the surrounding tissues without invading or infiltrating them) Yes (usually infiltrates and invades the adjacent tissues) Metastasis Absent Frequently present Nucleus of cells Nuclear variation in size (anisonucleosis) and shape minimal Nuclear variation in size and shape minimal to marked, often variable benign and malignant tumours Characteristics Benign tumours Malignant tumours Nuclear to cytoplasmic ratio Normal Increased Genome Diploid Range of ploidy Chromosomal abnormalities Infrequent Invariably present Retention of specialisation Loss of specialisation Differentiation Structural differentiation retained Functional differentiation (usually) Structural differentiation shows wide range of changes Functional differentiation often lost Function Usually well maintained Specialisation May be retained, lost or become abnormal benign and malignant tumours Characteristics Benign tumours Malignant tumours Boundaries Encapsulated or well circumscribed Poorly circumscribed or irregular Surrounding tissue Often compressed Usually invaded Secondary changes Occur less often Occur more often Pleomorphism Usually not present Often present Prognosis Local complications Death by local and metastatic complications … … … … … … Anaplasia  Anaplasia is lack of differentiation. Cells differentiate to a more immature or embryonic form.  Anaplasia is a characteristic feature of most malignant tumours.  An anaplastic cancer is the most malignant form with the poorest prognosis.  Malignant tumors are characterised by anaplastic cell growth.  Anaplasia  Anaplastic tumours may be the fastest growing form and have increased rate of mitosis.  At anaplastic stage, because the tumour is still contained within its original location called in situ and is not invasive, but it is potentially malignant. Carcinoma in situ (CIS) (in situ malignancy)  Carcinoma in situ (intraepithelial neoplasia) When the cytological features of malignancy are present but the malignant cells are confined to epithelium without invasion across the basement membrane is called carcinoma in situ or intraepithelial neoplasia. Cancer Biology  Cancer is a complex and potentially fatal disease that is considered a major world-wide public health problem.  Cancer is an umbrella term covering a plethora of conditions characterised by unscheduled and uncontrolled cellular proliferation.  Today, millions of people are living with cancer or have had cancer.  Unfortunately, there is no curative treatment once a cancer had spread and some interventions might even be more harmful !? BUT SOME TYPES OF CANCER ARE CURABLE!  Cancer Biology  The mechanism as to how a normal cell is transformed to a cancer cell is complex.  At different times attempts have been made to unravel this mystery by various mechanisms.  Currently a massive body of literature has accumulated to explain the pathogenesis of cancer at the molecular level. The development of cancer MULTIPLE STEPS TO CANCER Normal growth Hyperplasia Metaplasia ? Dysplasia Neoplasia Benign tumour Anaplasia Malignant tumour Normal cells may become cancer cells Cancer progression Mutations in multiple cancer genes are required for the development and progression of a single cancer Benign Tumour In situ cancer Invasive cancer Metastatic cancer Colon cancer as a multistep model of cancer development Colon Loss of tumour suppressor gene APC or other genes Loss of tumour suppressor gene p53 Activation of ras oncogene Colon wall Normal colon epithelial cells Small benign growth (polyp) Loss of tumour suppressor gene DCC Additional mutations Larger benign growth (adenoma) Malignant tumor (carcinoma) Cancer has a lot to do with cell signalling for growth and the pathways involved in cancer are very complex Iceberg concept Cancer Biology – GRADING AND STAGING OF CANCER  Grading and staging are the two systems to predict tumour behaviour and guide therapy after a malignant tumour is detected.  Grading is defined as the gross and microscopic degree of differentiation of the tumour. Grading is a measure of anaplasia.   Based on the cell of origin and on the anticipated behaviour i.e. benign or malignant, tumours can be classified. Cancer Biology – GRADING AND STAGING OF CANCER  Staging means extent of spread of the tumour within the patient. Different systems are in use for different cancer types.  TNM (primary tumour, lymph node and metastasis) cancer staging can be used in classification of malignant tumours. Why study Cancer Biology?  To investigate the biological differences between normal cells and cancer cells.  To understand the mechanisms that underlie fundamental processes such as cell growth, the transformation of normal cells to cancer cells and the mechanisms of invasion and metastasis of cancer cells. Why study Cancer Biology?  To understand the molecular pathogenesis of human cancers and to exploit this knowledge for the development of new therapeutics.  To develop a comprehensive understanding of the principles and practice of core topics in current areas of medical science. Why study Cancer Biology?  To understand the complexity and interactions involved in the regulation of gene expression and to interpret the molecular consequences of gene deregulation.  To evaluate the role of genetics in sporadic and familial human cancer. Why study Cancer Biology?  To expound on the mechanisms and consequences of acquired drug resistance in tumour cells.  To understand some of the mechanisms by which tumours may evade immune recognition and destruction. Hallmarks of Cancer  For cells to be able to initiate carcinogenesis successfully, they need to acquire a set of key cellular characteristics. A number of these key features, collectively referred to as the hallmarks of cancer, are required for cancer cells to survive, proliferate and disseminate successfully.  The hallmarks of cancer comprise several biological capabilities acquired during the multistep development of human tumours. Hallmarks of Cancer “characteristic properties of cancer cells” Hallmarks of Cancer 1. Sustaining proliferative signalling 2. Evading growth suppressors 3. Resisting cell death 4. Enabling replicative immortality 5. Inducing angiogenesis 6. Activating invasion and metastasis 7. Genome instability and mutation 8. Tumour-promoting inflammation 9. Deregulating cellular energetics 10. Avoiding immune destruction Sustaining proliferative signalling    Normal cells rely on positive growth signals from other cells. The most fundamental trait of cancer cells involves their ability to sustain chronic proliferation. Cancer cells, by deregulating proliferative signals (mitogenic signals*), become masters of their own destinies. * mitogenic signal: a signal which triggers cell proliferation Sustaining proliferative signalling Cancer cells can reduce their dependence on growth signals and acquire sustained proliferation by 1. Overproduction of growth factor ligands 2. Overproduction of growth factor receptors 3. Production of structurally altered receptors which are able to signal in absence of ligand binding 4. Activation of intracellular signalling pathway components so that signalling is no longer liganddependent Growth factors Growth factor receptors Cell wall Evading growth suppressors  Normal cells rely on antigrowth (growth suppression) signals to regulate cell growth. Cancer cells can become insensitive to antigrowth signals.  Most cellular growth suppression programmes are dependent on the action of tumour suppressor genes.  Mutations that result in stimulation of growth-stimulating pathways or deficiencies in growth-inhibiting pathways lead to increased cell division.  One mechanism for evading growth suppressors is downregulation of contact-mediated growth suppression (contact inhibition). Resisting cell death  When normal cells become old/damaged, they go through apoptosis (programmed cell death).  An important hallmark of many cancers is resistance to apoptosis, which contributes to the ability of the cells to divide uncontrollably.  Diminished apoptosis in tumour cells can be caused by several means. Resisting cell death  In normal tissues, cell proliferation is limited by terminal differentiation and counterbalanced by cell loss, often via apoptosis. Cell damage also elicits apoptosis or necrosis. Moreover, apoptosis can be induced in response to inappropriate proliferation or by cytotoxic immune cells.  Cancer cells must overcome the barriers presented by apoptosis and replicative senescence. The apoptotic response in cancers is inadequate or blocked. Likewise, cancer cells are in general ‘immortalised’ and proliferate beyond the limits of replicative senescence. Pathways of apoptosis Enabling replicative immortality    In normal cells, telomeres (the ends of chromosomes), get shorter with each cell division until they become so short that the cell can no longer divide. Cancer cells have the ability to overcome the boundaries on how many times a cell can divide. These limits are usually set by telomeres. In cancer cells, telomeres are maintained by telomerase, allowing the cell to divide an unlimited number of times. Angiogenesis    Angiogenesis is the formation of new blood vessels from pre-existing vessels. Angiogenesis is a normal process in growth and development as well as in wound healing. However, angiogenesis is also a fundamental step in the transition of tumours from a dormant state (benign) to a malignant state. Angiogenesis  Angiogenesis is a vital process in the progression of cancer from small, localised neoplasms to larger, growing and potentially metastatic tumours.  Thus, upregulation of angiogenesis is a key step in sustained tumour growth and may also be critical for tumour metastasis. The endothelial cells selectively express markers in the angiogenic blood vessels of tumours.    Angiogenesis is required for survival of the tumour, invasion and metastasis. The process of angiogenesis continues even as the tumour matures. To grow beyond 1 to 2 mm in diameter, a tumour needs an independent blood supply which is acquired by expressing growth factors that recruit new vasculature from existing blood vessels. Angiogenesis  As a tumour develops, its volume and size is limited by the availability of oxygen, glucose and other necessary metabolites from the existing vasculature. In order to maintain growth, new blood vessels are necessary to meet the metabolic demands of the tumour.  The arrangement of tumour blood vessels is often chaotic which results in regional variations in nutrient supply and removal of catabolites*. * Catabolite: metabolic by-product from breakdown processes. Angiogenesis  Tumour blood vessels show many differences from those in most normal tissues. Tumour capillaries are often longer than those in normal tissues and tend to be dilated and tortuous (convoluted). They are often quite leaky and blood flow can be erratic and prone to stasis, microhaemorrhage and can even reverse within individual vessels.  The leakiness of the blood vessels, combined with the lack of functional lymphatic vessels in tumours, leads to an increased interstitial fluid pressure within the tumour. Activating invasion and metastasis  Tumours may spawn pioneer cells that can invade adjacent tissues and travel to other sites in the body to form new tumours (metastasis). This capability allows cancer cells to colonise new areas where oxygen and nutrients are not limiting.  Invasion is the ability of cells to break through basement membrane and then spread into surrounding tissue and lymphatic/vascular channels. Spawn: seed Pioneer: creator; inventor; developer Activating invasion and metastasis  The ability of cancer cells to spread beyond the confinements of their tissue compartment (original site) into other parts of the same tissue and successively into neighbouring tissues (invasion) and distant organs (metastasis) is the defining property of malignancy.  in situ carcinoma → invasive carcinoma.  Invasion is characteristic of malignant cells. How do cancer cells invade and spread?  Normally, cells are constantly in contact with their surrounding cells and extracellular matrix (ECM) by means of their cell adhesion molecules (CAMs). Cell adhesion molecules (CAMs) include integrins (attaching cells to the ECM), cadherin-catenin complex (join cells together) and laminins (attaching cells to the basement membrane).  The absence or excess expression of CAMs in cancer cells allow them to break free from each other and spread in the tissues. Malignant cells do not adhere to the same extent as normal cells and also show a change in their interaction with surrounding stroma Altered synthesis of enzymes that breakdown basement membrane and stroma → role of matrix dissolving enzymes.   Role of matrix dissolving enzymes Different enzymes can modify stroma allowing cells to break through basement membrane and spread. Certain cancer cells secrete enzymes that dissolve the surrounding connective tissue and help them spread such as:  Collagenases  Matrix metalloproteinases (MMPs)  Hyaluronidase*  … * Hyaluronidase digests hyaluronic acid. Hyaluronic acid is a proteoglycan present in the extracellular matrix (ECM) and is important for the maintenance of tissue architecture. Depolymerisation of hyaluronic acid may facilitate tumour invasion. In addition, oligosaccharides of hyaluronic acid have been reported to induce angiogenesis. Metastasis  Metastasis is the ability of malignant cells to invade the lymphatics, blood vessels or cavities and spread to distant sites and establish secondary tumour mass.  The high mortality rates associated with cancer are caused by the metastatic spread of tumour cells from the site of their origin.  In fact, metastases are the cause of 90% of cancer deaths.  Metastasis causes 90% of deaths from solid tumours.  Not all circulating cancer cells will settle at a distant site and be able to grow. Metastasis process The process of metastasis can be summarised as: 1. 2. 3. 4. 5. 6. 7. Local invasion → epithelial to mesenchymal transition (EMT) Intravasation by cancer cells into the nearby blood and lymphatic vessels. Transit of cancer cells through the lymphatics and blood circulation (Circulating Tumour Cells – CTCs) Survival of cancer cells in the circulation. Escape of cancer cells from the lumina of blood and lymphatic vessels into the parenchyma of distant tissues (extravasation). The formation of small lesions of cancer cells (micrometastasis). The growth of micrometastatic lesions into macroscopic tumours (colonisation). Circulating Tumour Cells (CTCs) best defined as tumour cells originating from epithelial tissue i.e. circulating epithelial tumour cells because if you say CTCs it also means circulating haematologic tumour cells. Metastasis process Invasion EMT CTCs MET CTCs: circulating tumour cells EMT: epithelial to mesenchymal transition MET: mesenchymal to epithelial transition Routes of metastasis Cancers may spread to distant sites by Lymphatic spread Spread to local and distant lymph nodes is a frequent route of spread of carcinomas. 1. 2. Haematogenous spread Spread along body cavities and natural passages (coelemic spaces) Transcoelomic spread, along epithelium-lined surfaces, spread via cerebrospinal fluid, implantation. 3. Evading immune destruction  The immune system is responsible for recognising and eliminating cancer cells and therefore preventing tumour formation.  Evasion of the immune surveillance by weakly immunogenic cancer cells is an important emerging hallmark of cancer. Genome instability and mutation    Cancer cells achieve genome instability by increasing their mutability or rates of mutation, through increased sensitivity to mutagenic agents or breakdown of genomic maintenance machinery. Random genetic mutations may happen continuously throughout all cells of the body but cellular DNA repair mechanisms are so effective that almost all spontaneous mutations are corrected without ever producing phenotypic changes. However, in cancer cells the accumulation of mutations can be accelerated by compromising the surveillance systems that normally monitor genomic integrity and force genetically damaged cells into either senescence or apoptosis. Tumour-promoting inflammation   Immune cells infiltrate tumours and produce inflammatory responses which can paradoxically enhance tumourigenesis, helping tumours acquire the hallmarks of cancer. Necrosis has pro-inflammatory and tumour-promoting potential.  Necrotic cell death releases pro-inflammatory signals into the surrounding tissue microenvironment in contrast to apoptosis and autophagy which do not.  In the context of neoplasia, strong evidence suggests that immune inflammatory cells can be actively tumour promoting. Necrosis