Neoplasia and Neoplastic DiseasesFaraza Javed

M.Phil Pharmacology

Neoplasia

Neoplasia is defined as:

" An abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of the normal tissues and persists in the same excessive manner after cessation of the stimuli that evoked the change."

One in three people in the Western world develop cancer and one in five die of the disease.

There are approximately 200 types of cancer, each with different causes, symptoms and treatments.

In 2007, 297,991 people were newly diagnosed with cancer in the UK.

An individual's risk of developing cancer depends on many factors, including age, lifestyle and genetic make-up.

Causes of Neoplasia

Neoplasia results due to: Genetics Environmental Causes

Genetics: A change in the DNA sequence that can be inherited

from either parent (Inherited) OR A change in the DNA sequence in cells other than

sperm or egg (Somatic)

Somatic

InheritedBoth

Only 5 –10% of cancer cases have a clear hereditary component. Even in those cases where susceptibility is clearly inherited, somatic changes are required for cancer to develop.

External Causes: UV Radiations X-Rays Tobacco Smoke Alcohol Fatty Food Human Papilloma Virus (HPL) Human Immunodeficiency Virus (HIV)

Nomenclature

In common medical usage, a neoplasm often is referredto as a Tumor, and the study of tumors is called Oncology.

Among tumors, the division of neoplasms into Benign and Malignant categories is based on a judgment of a tumor’s potential clinical behaviour.

1. Benign Tumor:Attaching the suffix-oma to the cell of organ and derived tissue cell + oma/ cell + morphologic character + oma

e.g. adenoma of thyroid, ovarian cyst adenoma.

2. Malignant Tumor:Malignant tumors are collectively referred to as Cancers. These are classified as Carcinoma and Sarcoma.

Carcinoma:Malignant tumors of Epithelial cell origin/ name of

organ and derived tissue/ cell + morphologic feature + carcinoma

e.g. adenocarcinoma of thyroid, ovarian cyst adenocarcinoma.

Sarcoma:Malignant tumors arising in Mesenchymal tissue (other than epithelial cell) or its derivatives / The name of organ and derived tissue/ cell + sarcoma

e.g. Angiosarcoma.

3. Teratomas: Tumors containing mature or immature cells or tissues representative of more than one germ layer and sometimes all the three layers.

e.g. Ovarian Teratoma

4. Hamartoma: Tumor-like malformation composed of a haphazard arrangement of tissues indigenous to the particular site, which is totally benign.

e.g. Pulmonary Hamartoma

5. Mixed tumors:

Tumors which derived from one germ layer may

undergo divergent differentiation (involve more than 1

type of tissue) creating so called mixed tumor.

e.g. Mixed tumor of salivary gland and Parotid gland.

Characteristics of Neoplasm

There are four fundamental features by which benign and malignant tumors can be distinguished: Differentiation and Anaplasia Rate of growth Local invasion Metastasis

Differentiation And AnaplasiaDifferentiation- Extent to which neoplastic cell resemble normal cell.

Anaplasia- Lack/ Loss of (structural and functional) Differentiation of normal cell.

Dysplasia- Disordered Growth. Loss in the uniformity of individual cell and their architectural orientation. It represents a state b/w hyperplasia and carcinoma. Does not necessarily progress to cancer.

Benign tumors resemble the tissue of origin and are well differentiated.

Malignant tumors are poorly or completely undifferentiated (anaplstic).

Rate of Growth Benign tumors are slow growing, whereas malignant

tumors generally grow faster.

Local Invasion

A Benign neoplasm remains localized at its site of origin. It does not have the capacity to infiltrate, invade or metastasize to distant site. Most of tumor develop an enclosing fibrous capsule that separates them from the host tissue.

Cancer grow by progressive infiltration, invasion and penetration of surrounding tissue. They do not develop well defined capsule.

Next to the development of metastases, local invasiveness is the most reliable feature that distinguishes malignant from benign tumor.

Metastasis Metastasis are secondary implants discontinuous with

the primary tumor and located in remote tissues.

Benign tumor remain localized to the site of origin, whereas malignant tumor locally invasive and metastasize to distant site.

Molecular Basis of Cancer

Cell CycleThe process of replicating DNA and dividing a cell can be described as a series of coordinated events that compose a “cell division cycle.’’

A set of checkpoints that monitor completion of critical events, leading to cell division and duplication that produce two daughter cells.

1st type of cell cycle regulation, checkpoint control, is more supervisory. Cell cycle checkpoints sense flaws in critical events such as DNA replication and chromosome segregation. When checkpoints are activated, for example by underreplicated or damaged DNA, signals are relayed to the cell cycle-progression machinery. These signals cause a delay in cycle progression, until the danger of mutation has been averted.

2nd is the cascade of protein phosphorylations that relay a cell from one stage to the next. Cyclin-dependent kinases (CDKs) are a family of protein kinases discovered for their role in regulating the cell cycle. They are also involved in regulating transcription, mRNA processing, and the differentiation of cells. CDK binds a regulatory protein called a cyclin, form cyclin-CDK complex and phosphorylate their respective substrate and regulate cell cycle.

Receptors Protein Function

CDK1 Cyclin A Regulate all cell cycle stages

Cyclin B M phase

CDK2 Cyclin A All cell stages, G2 phase

Cyclin E S phase

Cyclin D G1 phase

Regulatory phosphorylation and dephosphorylation fine-tune the activity of CDK–cyclin complexes, ensuring well-delineated transitions between cell cycle stages.

Mutation or deregulation of this process has been associated with many types of cancers i.e. uncontrolled cell proliferation. Hence, CDKs are considered as a potential target for anti-cancer medication.

Molecular Basis of CancerCarcinogenesis is a multistep process resulting from the accumulation of multiple genetic alterations that collectively give rise to the transformed phenotype. DNA Repair Gene Oncogenes Tumor Suppressor Gene Genes Regulating Apoptosis

DNA Repair Gene DNA repair genes code for proteins whose normal

function is to correct errors that arise when cells duplicate their DNA prior to cell division.

DNA repair genes are active throughout the cell cycle, particularly during G2 after DNA replication and before the chromosomes divide.

Mutations in DNA repair genes can lead to a failure in repair, which in turn allows subsequent mutations to accumulate.

If the rate of DNA damage exceeds the capacity of the cell to repair it, the accumulation of errors can overwhelm the cell and result in cancer.

A few important DNA repair genes include BRCA1 and BRCA2 gene.

Oncogenes An oncogene is a proto-oncogene that has been

mutated in a way that leads to signals that cause uncontrolled growth.

Oncogenes are "gain of function" genes. They gain the ability to drive non-stop growth. In spite of their dominant activities, a single mutated oncogene usually isn't enough to cause cancer all by itself because tumor-suppressor genes are acting to put the brakes on to keep cell growth from getting out of control.

Oncogenes aren't usually involved in inherited forms of cancer because most occur as somatic mutations and can't be passed from parent to child.

Example of Oncogenes include HER-2, RAS, SRC, hTERT.

Tumor Suppressor Gene

Tumor suppressor genes in normal cells act as braking signals during phase G1 of the cell cycle, to stop or slow the cell cycle before S phase. If tumor-suppressor genes are mutated, the normal brake mechanism will be disabled, resulting in uncontrolled growth, i.e. cancer.

Mutations in tumor-suppressor genes cause loss-of-function. Loss-of-function mutations generally only show up when both copies of the gene are mutated. In other words, if a pair of tumor suppressor genes are lost or mutated, their functional absence might allow cancer to develop.

Individuals who inherit an increased risk of developing cancer often are born with one defective copy of a tumor suppressor gene.

Because genes come in pairs (one inherited from each parent), an inherited defect in one copy will not lead to cancer because the other normal copy is still functional. But if the second copy undergoes mutation, the person then may develop cancer because there is no longer any functional copy of the gene.

P53, Rb, APC are few examples of tumor suppressor genes.

Genes Regulating ApoptosisApoptosis is the death of cells which occurs as a normal and controlled part of an organism's growth or development.

Mutations of these genes that regulate apoptosis result in evasion of Apoptosis, would also be a factor in carcinogenesis.

Genes involve in regulation of Apoptosis include BCL2, p53 and MYC.

Hall Marks of Cancer

Each cancer gene has a specific function, the dysregulation of which contributes to the origin or progression of malignancy. It is best, therefore, to consider cancer related genes in the context of several fundamental changes in cell physiology, the so­called hallmarks of cancer, which together dictate the malignant phenotype.

Self-Sufficiency of Growth Signals

Normal cells require external growth signals (growth factors) to grow and divide. These signals are transmitted through receptors that pass through the cell membrane. When the growth signals are absent, cell stop growing.Cancer cells do not need stimulation from external signals (in the form of growth factors) to multiply.Cancer cells can grow and divide without external growth signals.

The best documented examples of over expression involve the epidermal growth factor (EGF) receptor family. These signaling proteins couple growth factor receptors to their nuclear targets. They receive signals from activated growth factor receptorsand transmit them to the nucleus, either through second messengers or through a cascade of phosphorylation and activation of signal transduction molecules.

Two important members in this category are RAS and ABL.

RAS is a member of a family of small G proteins that bind [GTP] and [GDP], similar to thelarger trimolecular G proteins. Due to mutation RAS is locked into its active GTP form and the cell is forced into a continuous proliferating state.

Activated ras then causes the activation of a cellular kinase called RAF­1. RAF­1 kinase then phosphorylates another cellular kinase called MEK. This cause the activation of MEK. Activated MEK then phosphorylates another protein kinase called MAPK causing its activation i.e MAP Kinase Pathway and ultimately causes changes in gene transcription.

RAF and MEK are targeted sites for anti cancer drugs.

Insensitivity to Anti-Growth Signal

The growth of normal cells is kept under control by growth inhibitors in the surrounding environment, in the extracellular matrix and on the surfaces of neighboring cells. These inhibitors act on the cell cycle clock, by interrupting cell division in the interphase.

Cancer cells are generally resistant to these growth­preventing signals.

Evading Apoptosis Cells are born, live for

a given period of time and then die

APOPTOSIS

Physiological cell death Cell suicide Cell deletion

Programmed cell death

When ligand bind to receptor tyrosine kinase, receptor get activation and this signaling activates PI3K which catalyses phosphorylation of inositol phosphates (PIP2 to PIP3). These act as second messengers and recruit molecules such as Akt kinase to the cell membrane. AKT Kinase phosphorylate BAD and Forkhead Proteins that promote cell survival.

BAD (Pro­apoptotic Protein) is activated when it is non phosphorylated and hence cause apoptosis. AKT causes phosphorylation of BAD that results in antiapoptotic effect.

Receptor Tyrosine Kinase Inhibitors or more precisely AKT inhibitors are now developed as an anticancer agents.

Limitless Replicative Potential

Mammalian cells have an intrinsic program, the Hayflick Limit, that limits their multiplication to a certain limit.

This limit can be overcome by disabling their pRB and p53 tumor suppressor proteins, which allows them to continue doubling until they reach a stage called crisis that results in emergence of an immortalized cell that can double without limit.

The counting device for cell doublings is the telomere, which loses DNA at the tips of every chromosome during each cell cycle. Many cancers involve the up regulation of telomerase, the enzyme that maintains telomeres.

Sustained Angiogenesis Angiogenesis is the growth of blood vessels from the

existing vasculature. It is also a fundamental step in the transition of tumors from a dormant state to a malignant one.

Tumors cannot grow beyond a certain size, generally 1–2 mm3, due to a lack of oxygen and other essential nutrients. HIF­1(Hypoxia inducible factor) act as a transcription factor to activate the GF.

To supply nutrients and oxygen, tumors induce blood vessel growth (angiogenesis) by secreting various growth factors (e.g. VEGF). Growth factors such as bFGF and VEGF can induce capillary growth into the tumor.

Angiogenesis is involved in the growth of cervix, breast and melanoma tumors. Anti­VEGF antibodies slowed the growth of tumors in mice. Anti­angiogenesis compounds are under investigation as drugs to treat cancer.

Tissue Invasion and MetastasisCancer cells can break away from their site or organ of origin to invade surrounding tissue and spread (metastasize) to distant body parts.

Normal cell–cell interactions is regulated, through Cell–cell adhesion molecules (CAMs) Integrins

CAM and Integrin becomes altered and results in metastases as in lung cancer and colorectal cancer and allow Primary tumor masses spawn "pioneer cells" that invade adjacent tissues, and may then travel to distant sites to establish metastases.

Neoplastic Diseases

Lungs Cancer Lung cancer is the number one cancer killer of men

and women. Most cases of lung cancer are related to cigarette smoking. Cancer may be caused by acombination of genetic factorsand exposure to radon gasor other forms of air pollutionincluding second­hand smoke.

Symptoms Persistent Cough Blood-streaked Sputum Chest Pain Fever Fatigue Wheezing and Shortness of Breath Pneumonia

Treatment

Chemotherapy Radiotherapy Surgery

Breast CancerCancer of the breast is the 2nd leading cause of cancer deaths in women.

Risk factors for developing breast cancer include: Obesity Alcohol Consumption Hormone Replacement Therapy Ionizing Radiation and Having Children late or not at all

Symptoms

Lump in the breast Dimpling of skin Skin irritation Red Scaly Patch on Skin Swollen Lymph Nodes Constant Pain in breast and armpit area

Treatment

Lumpectomy Radical Mastectomy Chemotherapy Hormone Blocking Therapy Monoclonal Antibodies Radiotherapy

Colon and Rectal Cancers

Third most common cancers in men and women but 90% of colorectal cancers are preventable.

Risk factors: Age over 50 years, obesity, family history of colon or rectal cancer, diet high in fats and low in fiber, smoking, high alcohol consumption, lack of exercise, inflammatory bowel disease and ulcerative colitis.

It typically starts as a benign tumor which over time becomes cancerous.

Symptoms

Nausea and Vomiting Change in bowel movements Loss of appetite Blood in Stool Worsening Constipation Weight Loss

Treatment

Chemotherapy Radiotherapy Surgery

Skin CancerLong-term sun exposure (UV Radiations) can result in skin cancer. Malignant melanoma is the deadliest form of skin cancer.

Use the ABCD rule to detect melanoma. Asymmetry: Half of a mole does not look like the

other half Border irregularity: The edges are uneven Color: Pigmentation is not uniform Diameter: Larger than a pea

Treatment

Chemotherapy Surgery Skin Grafting

Prostate CancerProstate cancer is the carcinoma of prostate gland that may spread to other parts of the body particularly bones and lymph nodes.

Symptoms: Weak or interrupted urine flow Blood in urine Nocturia, Dysuria Pain in Pelvis

Treatment

Chemotherapy Radiotherapy Prostectomy

LeukemiaLeukemia is a group of cancers that usually begins in the bone marrow and results in high number of abnormal white blood cells. There are 4 main types of leukemia: Acute Lymphoblastic Leukemia (ALL) Acute Myeloid Leukemia (AML) Chronic Lymphoblastic Leukemia (CLL) Chronic Myeloid Leukemia (CML)

Symptoms Bleeding and Bruising Problems Lack of Blood Platelets Pinprick Bleeds (Petechiae) on Skin Anemia Swollen Lymph Nodes Weight Loss Opportunistic Infections

Treatment

Chemotherapy Radiotherapy Bone marrow transplantation

Cancer’s Seven Warning Signals

Awareness ProgramsRibbon Awareness Campaign

You can be a victim of cancer or a survivor of cancer.

It’s a mindset.

Hope is the Physician of Each Misery

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Hahn, W. C. & Weinberg, R. A. Rules for making human tumor cells. New England Journal of Medicine 347, 1593–1603.

Bric, A., Miething, C. et al. Functional identification of tumor-suppressor genes through an in vivo RNA interference screen in a mouse lymphoma model.Cancer Cell 16, 324–335 (2009).

Hallmarks of Cancer, Cancer Research UK Science Update blog, November 2010.

Lazebnik Y (April 2010). "What are the hallmarks of cancer?". Nat. Rev. Cancer 10(4): 232–3.

Hams NL, Jaffa ES, Stein H et al. A revised European-American classification of lymphoid neoplasms: A proposal from the International (2010); 84: 1361-92.