Love or Infatuation?

Heya, freinds!

Sorry for not updating my blog for a very long time. It seems like an eternity. A lot of things have come and gone. On Kenneth’s birthday, Penny, Chareli, Petrina, Kenneth and me went to watch a movie in cine. It was X-men 3. I loved that movie very much. I gave kenneth a gifted keychain with his name in it. I hope he likes it. I remember once that he mentioned he didn’t like a particular shade of green and the keychain was in that particular shade of green.

I recently read a wonderful story from the chicken soup for the soul book. It’s a short one so i’ll just type out the whole prose:

Love or Infatuation?

Infatuation is instant desire. It is one set of glands calling to another. Love is friendship that has caught fire. It takes root and grows-one day at a time.
Infatuation is marked by a feeling of insecurity. You are excited and eager but not genuinely happy. There are nagging doubts, unanswered questions, little bits and pieces about your beloved that you would just as soon not examine too closely. It might spoil the dream.
Love is quite understanding and the mature acceptance of imperfection. It is real. It gives you strength and grows beyond you-to bolster your beloved. You are warmed by his presence, even when he is away. Miles do not separate you. You want him nearer. But near or far, you know he is yours and you can wait.
Infatuation says, “We must get married right away. I can’t risk losing him.”
Love says, “Be patient. Don’t panic. Plan your future with confidence.”
Infatuation has an element of sexual excitement. If you are honest, you will admit it is difficult to be in one another’s company unless you are sure it will end in intimacy.
Love is the maturation of friendship. You must be friends before you can be lovers.
Infatuation lacks confidence. When he’s away, you wonder if he’s cheating. Sometimes you check.
Love means trust. You are calm, secure and unthreatened. He feels that trust, and it makes him even more trustworthy.
Infatuation might lead you to do things you’ll regret later, but love never will.
Love is an upper. It makes you look up. It makes you think up. It makes you a better person than you were before.

I think it tells everything that a person needs to know about the differences between love and infatuation…

17minutes and 14 seconds

Yes, that was my timing for napfa on thursday. Pretty bad ya? Well, i’m happy that i did my best. Saif Ali Khan was so nice that he changed my timing to 17.10 so that i would pass. But still i have to retake my test next term. Once again, he was kind enough to give me more time to train and gain more confidence.

I call him Saif Ali Khan because he looks like a bollywood actor. He’s also my favourite actor. Here’s his photo.

Well, he kind of looks like Mr Derick Ho. Right?

Sometimes, i feel that i’m missing the connection with nature. I’ve never been to a park, or gone for a camp in the wild. Not even to the chinese garden near my house. I wonder when am i going to give my time more to nature and relaxation. Probably never in my lifetime. After A’ levels, i would get into medicine, and i would be very busy with my studies that i would never even have time for other activities in my life for until a time in my life.

I want to do something worthwhile in my life, something for the welfare of others. I love children very much. I want to do something for the welfare of the children and therefore chose medicine as my career. I really do hope that i could get into medicine.

I’ll blog tomorrow. Bye for now…

Leukemia

Heya!!

I was thinking about the poor children in the Children’s Cancer Association in Singapore. I bought a bouquet of dozen paper-made roses for $10. A kind of donation i made for them. Most of them, i presume, suffer from leukemia, a kind of blood cancer. Let’s look at it.

Leukemia is a form of cancer that begins in the blood-forming cells of the bone marrow – the soft, inner part of the bones. Leukemia – which literally means “white blood” in Greek – occurs when there is an excess of abnormal white blood cells in the blood. Known as leukocytes, these cells are so plentiful in some individuals that the blood actually has a whitish tinge.

Under normal circumstances, the blood-forming, or hematopoietic, cells of the bone marrow make leukocytes to defend the body against infectious organisms such as viruses and bacteria. But if some leukocytes are damaged and remain in an immature form, they become poor infection fighters that multiply excessively and do not die off as they should.

The leukemic cells accumulate and lessen the production of oxygen-carrying red blood cells (eythrocytes), blood-clotting cells (platelets), and normal leukocytes. If untreated, the surplus leukemic cells overwhelm the bone marrow, enter the bloodstream, and eventually invade other parts of the body, such as the lymph nodes, spleen, liver, and central nervous system (brain, spinal cord). In this way, the behavior of leukemia is different than that of other cancers, which usually begin in major organs and ultimately spread to the bone marrow.

There are more than a dozen varieties of leukemia, but the following four types are the most common:
acute lymphocytic leukemia (ALL),
acute myelogenous leukemia (AML),
chronic lymphocytic leukemia (CLL), and
chronic myelogenous leukemia (CML).

Acute leukemias usually develop suddenly, whereas some chronic varieties may exist for years before they are diagnosed.

However, many people think that leukemia is a childhood disease. Yet, it strikes 10 times as many adults as children.

This high-power microscopic view of a blood smear from a person with classical CML shows predominantly normal-appearing cells with intermediate maturity.

All the cells in this field are hairy cells. The cell membranes appear irregular and serrated. The cytoplasm stains light blue (black arrows). The nuclei tend to be irregular (red arrows).

I find it interesting. Anyhow, that’s all for now. Tata!!

Heya,

i’m really very scared and damn stressed because tomorrow is my napfa 2.4km run. I don’t know how exactly am I going to survive that run. I feel extremely scared to think of it. If I do well and pass, depending on my will power, I shall be very happy cos i don’t have to do napfa for the rest of my entire life. If I fail, well, i’ve got to try harder. However, the situation this year is much better than last year, so i have no doubt abt me doing well.

I asked my secondary school friend Arjunan for tips on running. He gave me a lot of good advice. We had a lengthy chat yesterday night over the phone. So if i did well, much of the credit shall go to him. He is a really nice person. Hope i could meet him sometime, like in a get-together or something.

Today, i feel so tired now, that i hardly have time to go read up on more cancer stuff and post it. So i think i’ll just leave it here. I feel that at this point, my blog looks very boring cos it concentrates more on cancer and cancer and cancer. Phew!! I’ll try to post more lively stuff, such as more things about myself. This friday is a holiday and so is next tuesday!! So I have more time to study and blog…

Tomorrow is biology test, but while thinking about the napfa test, i don’t have the mood to study at all. I think i’ll just do my best in the test. I can’t concentrate on the test while my mind is entirely on the napfa test. My aim for the run tomorrow, is to run with a consistent pace and try very very very hard not to walk at all. I’ve to keep telling these two things in my mind again and again like a mantra while i’m running. also, i’ve been hydrating myself today with plenty of water, as adviced by Arjunan.

Ok, I blog tomorrow. Hope i could come up with some good news and write “yey! i did it. my timing for the run was good and i got a silver for my run!!!”

See ya!!!

On-going research around the world

Heya!

There are many countries which are involved in intense cancer research. Cancer is a widespread disease, which can occur to anyone, anytime. Nobody knows the cause nor the actual mechanism of events that lead to cancer, or neoplasm, as is the technical term. A lot of expertise from various areas of research ranging from genetics to structural biology are required to solve this mystery of cancer. I have taken the effort to make some list of on-going research only in UK, Institute of Cancer Research.

Cancer Research UK Centre for Cancer Therapeutics

Analytical Technology and Screening Team

Team Leader:
Dr Wynne Aherne
Location: Haddow Laboratories, Sutton

One of the key steps in target-directed cancer drug discovery is the identification of small molecule chemicals (hits) with activity against validated target proteins. This can be achieved by high throughput screening of large compound collections using appropriate assay formats. The role of the Analytical Technology and Screening Team is to run screens on selected cancer drug targets, and with others, to carry out the initial characterisation of the hits obtained. During the last year, screens completed include those for CHK1, CHK2, p70S6kinaseand HSP70, The Team is not only responsible for the high throughput screening but is also involved in the development of secondary and mechanistic assays used in other phases of the drug discovery process in which the pharmacological and drug-like properties of the hits are optimised.

Cell Cycle Control Team

Team Leader:
Dr Michelle Garrett
Location: Haddow Laboratories, Sutton

One of the principal characteristics of human cancer is the ability to proliferate in an uncontrolled manner. At the heart of cell proliferation is the cell division cycle and, when not regulated correctly, this process can be one of the underlying causes of cancer. The main aims of the Cell Cycle Control Team are:

(i) to further our understanding of how signalling pathways regulate the mammalian cell division cycle through the cyclin dependent kinase (CDK) family of serine/threonine kinases and to use this knowledge to identify and validate cell cycle regulators as targets for therapeutic intervention in cancer

(ii) to participate in drug discovery and development projects that can utilise our expertise in signalling pathways and cell cycle regulation

In particular, we are interested in the cyclin D-dependent kinases CDK4 and CDK6, which associate with the D-type cyclins to control G1 progression through phosphorylation of the tumour suppressor protein, pRb. Most human cancers contain genetic alterations that affect these kinases, their regulators including the D-type cyclins or pRB itself. In addition they act as a key integration point between extracellular signalling pathways such as those governed by Ras and PI3 kinase/protein kinase B and the cell division cycle. Thus, understanding the molecular basis of the CDK/cyclin D/pRb pathway and its regulation will be important in the identification of novel targets for new cancer treatments. We are also participating in four drug discovery and development projects. These are on PKB, pRb phosphorylation and the CHK1 and CHK2 cell cycle checkpoint kinases.

Cell Growth Regulation and Angiogenesis Team

Team Leader:
Dr Margaret Ashcroft
Location: Haddow Laboratories, Sutton

Like all normal tissues in the body, cancer cells within a tumour mass need oxygen and nutrients to grow and expand. A growing tumour mass expands beyond the microscopic level by developing its own blood supply by stimulating the growth and invasion of surrounding blood vessels into the growing tumour mass. This process is known as angiogenesis. Hypoxia-inducible factor (HIF) is a transcriptional complex that is central to mediating angiogenesis and tumour progression by upregulating specific targets such as vascular endothelial growth factor (VEGF). The main focus of the Cell Growth Regulation and Angiogenesis Team is to gain a better understanding of the molecular mechanisms underlying HIF regulation in normal and tumour cells, as a basis for the development of new cancer therapies.

Clinical Pharmacology and Trials Team

Team Leader:
Professor Ian Judson
Location: Sycamore House & Haddow Laboratories, Sutton

The Clinical Pharmacology and Trials Team is responsible for the study of the preclinical and clinical pharmacology of new anticancer agents developed in the Centre and for their early clinical trials. Such investigations may include the study of mechanisms of action and resistance, toxicology, pharmacokinetics, early dose-finding studies and the development of pharmacodynamic biomarkers for the measurement of drug action in tumour and surrogate tissues. These may be molecular assays or functional imaging studies. The emphasis is increasingly on hypothesis-testing clinical trials of agents acting on new molecular targets including cell signalling, cell survival, the cell cycle control machinery, chromatin modulation and angiogenesis.

In addition to studying the pharmacokinetics of agents in clinical trials, such as 17AAG, 17DMAG and abiraterone, Dr Florence Raynaud manages a group that evaluates the preclinical drug metabolism and pharmacokinetics (DMPK) of novel chemicals under development in the Centre. Early assessment of DMPK allows liabilities to be identified and the early implementation of strategies to optimise drug-like properties. The team is also interested in the development of novel PI3K inhibitors in collaboration with PIramed Ltd.

Gene and Oncogene Targeting Team

Team Leader:
Professor Caroline Springer
Location: Haddow Laboratories, Sutton

Gene targeting
Conventional cytotoxic chemotherapy has often suffers from the shortcoming that it es results in serious side effects. Antibody- or gene-directed enzyme prodrug therapy (ADEPT or GDEPT) aim to prevent this problem. In ADEPT and GDEPT the cytotoxic drugs have been converted into non-toxic prodrugs that do side effects. An enzyme capable of regenerating the drug from the prodrug is targeted to the tumour either by coupling the enzyme to an antibody that binds selectively to tumours (ADEPT), or by having the gene for the enzyme expressed by a tumour selective gene vector (GDEPT). Our aim is to express the prodrug-activating enzyme carboxypeptidase G2 (CPG2) in replicating adenoviral vectors, and to use these vectors to target CPG2 to tumours following injection either intravenously, or directly into the tumour. CPG2 has advantages over other enzyme prodrug converting A/GDEPT systems in that it releases a drug directly from the prodrug with no further cellular processing requirements. In addition, a large number of prodrugs can be designed that are converted to a range of different classes of drugs. Thus the prodrug/drug system selected can be tailored for the tumour type. We intend to administer prodrug following CPG2 expression in the tumours so it will be activated to cytotoxic drug selectively in the cancer cells. . The adenoviruses have been modified so that they are no longer pathogenic. . Replicating adenoviruses have been modified so that they can target specific tumour types, such as liver, , and colon. We have measured ratios of CPG2 activity of between 1,000:1 and 10,000:1 in tumour:liver, where liver is the next highest tissue after tumour to be targeted. We have demonstrated therapeutic efficacy in two human hepatoma models and a GDEPT clinical trials has just been approved with this system.

Oncogene targeting
The Cancer Genome Project has identified mutations in the enzyme B-RAF as its first major discovery. Mutations are present in 70% of melanomas, 10% of colorectal cancers and a smaller number of other cancers including early ovarian cancer. The mutations lead to activation of this enzyme, resulting in the tumour cell being in a state of continual growth. We havediscovered ipotent inhibitorsof B-RAF, with selectivity for the mutant form for use in malignant melanoma and potentially other tumour types. Inhibitors of B-RAF should reverse the cells’ tumour-forming characteristics, and probably will induce the cells to self-destruct.

Signal Transduction and Molecular Pharmacology Team

Team Leader:
Professor Paul Workman
Location: Haddow Laboratories, Sutton

This Team has two major complementary roles:
To understand the molecular mechanism of action of drugs that affect, or are affected by, signal transduction pathways that regulate proliferation, cell cycle and survival in cancer cells
To discover and develop innovative new drugs that act on novel molecular targets, defined by the genomics and molecular pathology of cancer.

The Team is particularly involved in the development of inhibitors of the heat shock protein 90 molecular chaperone, PI3 kinase and cyclin-dependent kinases. In addition we are interested in applying gene expression microarray and RNAi technology to understand the cellular pharmacology of molecular therapeutics and existing cancer drugs.

Target Discovery and Apoptosis Team

Team Leader:
Dr Spiros Linardopoulos
Location: Chester Beatty Laboratories, London

Chromosomal abnormalities are a hallmark of human cancer, reflecting the deleterious consequences of the gain or loss of genetic information. These abnormalities may be a consequence of tumour progression, mis-segregated chromosomes and aneuploidy. The fidelity of chromosome segregation is monitored by mitotic checkpoints that delay entry into mitosis until a functional centrosome is present. During this complex process, protein kinases play important roles in promoting or retarding transitions between different stages and checkpoints of the cell cycle. We aim to further understand mitotic control and use this information to identify and validate mitotic regulators as targets for cancer therapy. Currently one of our targets is the STK15 (Aurora2) gene, a mitotic kinase which has been found to be amplified in more than 50% of primary colorectal cancers and 12% of primary breast tumours as well as in breast, ovarian, colon, prostate, neuroblastoma and cervical cell lines. Thus, STK15 represents an attractive target for anticancer drug discovery. An additional field for identification and validation of genes involved in cancer is programmed cell death, also known as apoptosis. Apoptosis represents the defence mechanism of the cell with accumulated oncogenic mutations. Thus, defects in apoptotic signalling are thought to play an important role in the development of different types of cancers. It is not a surprise that the cell cycle and apoptosis are often deregulated in tumours. Therefore, they represent an attractive field for drug target discovery.

Tumour Biology and Metastasis Team

Team Leader:
Dr Suzanne Eccles
Location: McElwain Laboratories, Sutton

The major problem in cancer therapy is the treatment of disease that has invaded normal tissues and spread to secondary sites (metastasis). Our main aims are to understand more about the molecular mechanisms of tumour progression, and to develop better models to investigate the therapeutic potential of novel agents for translation into the clinic. Many of the signalling pathways and molecular processes used by tumour cells during invasion are also utilised by endothelial cells during neoangiogenesis (the process of development of new blood and lymphatic vessels on which tumour growth and spread depends). Recognising key ‘nodal points’ in these pathways will enable us to develop dual function inhibitors which can target both tumour cells and activated endothelial cells. Our work falls into two parts:

Investigation of signalling pathways in invasion and angiogenesis and their potential as targets for therapy;

Evaluation of markers of metastatic potential (and organ site selectivity) in human cancers.
We are also actively evaluating the therapeutic activity of a wide range of molecular therapeutics in in vitro and in vivo models relevant to human cancer.


I know that they are all very long deacriptions of the research work they are doing. Even I myself have not taken the time to read them thoroughly cos i have no time today. I’ve got to go back and do an AQ question for tomorrow. See Ya!

My sketches





Hello!

These are my sketches of Disney Princesses that i drew in my sketch book. This is one of my hobbies and i enjoy doing it cos it gives me relaxation and a sense of achievement. I want to draw more disney characters like Bambi, Pooh and friends and Mickey and friends. Hope you like it…

See ya!!
Priya 🙂

Lalalala…PKB

Heya!

Today was a great day! I went shopping with two of my best friends, Shu Hui and Kasturi. We were looking for a pair of shoes for Bing Hui, my another best friend, cos its her birthday, in a few more days. Well, i used this opportunity to also buy something for my dear dear mum. Mother’s day is coming soon, on 14th May. And also gifted a name for Kenneth, my classmate and friend. His birthday is coming soon too, on 25th May. It may seem that the date is faraway but i’m really busy this week and every other week. Plus, i have this bio test coming up on thursday. And my 2.4km run after the test. ooohf!! Wow! i feel really stressful at this moment. What should i do? Meditation is hardly helping now, cos there’s no time for meditation at all!!

Everytime i post an entry, i make sure that i also post something about what i’ve learned about cancer research and the advancements in it. This will serve me as a guide in my future. I’m sure it will. Today I read something about how the most important cell-signalling pathway for cell proliferation and survival can horribly go wrong in a cancer cell. Here is the excerpt from the Institute of Cancer Research.

PKB and cyclin D1

The protein PKB (also known as AKT) is part of a signalling pathway in the cell that promotes both cell proliferation and survival. This pathway receives signals from the external environment via a receptor at the cell surface, which then relays the signal to a protein complex known as PI3 kinase. PI3 kinase then produces a chemical, PIP3, that binds to and promotes activation of PKB. Once active, PKB sends signals throughout the cell via interactions with other proteins to promote both proliferation and survival. A key downstream target of PKB is a protein known as cyclin D1, which is an important regulator of cell proliferation and currently is under investigation in our laboratory. PKB acts on proliferation by regulating the amount of cyclin D1 in the cell (Figure 2). When PKB is actively sending signals throughout the cell, the level of cyclin D1 will increase, leading to uncontrolled cell proliferation, as in cancer. When PKB is switched off, the level of cyclin D1 in the cell will decrease and cell proliferation will cease.

In particular, the receptors that relay signals to the PI3 kinase/PKB pathway (see Figure 2) are overexpressed in lung and breast cancer, whilst genetic alterations that cause misregulation of PI3 kinase itself and the chemical messenger it produces have been discovered in colon, breast, prostate and ovarian cancer. PKB is also overexpressed in a number of tumour types.
Overexpression of cyclin D1 is associated with a variety of cancer types and contributes to the development of cancer. For example, overexpression of cyclin D1 has been associated with the development of breast cancer. These discoveries have led us to initiate a major programme to discover and develop inhibitors of PKB for the treatment of cancer.


Yey, today i’ve learned something new!! Tata for now!!

Apoptosis and me

Heya!

Today was a slacky day, deprived of any GP lesson. Wow! I’m so happy. I have used ‘happy’ so many times. But i really have a lot of worries currently in my mind. My short-term worry is about passing my final-NAPFA test next week. I would be free to follow my own fitness regime after NAPFA. I pray to God everyday that the weather on my 2.4km running-day should be cold and drizzling if possible. Oh pls pls pls God.

Oh well, do i have any choice? I have to run NAPFA. And the chances of me passing depends on my will power and motivation on that day. I should try very hard to run all the way. But i wonder how the ordeal to pass the cheering class of boys for each and every 6 rounds would be like. I would love it if someone runs with me all the way. But i don’t want to trouble anyone. I’m better off with me motivating myself.

I was reading an article on apoptosis, which is cell death. Below is the excerpt from the Institute of Cancer Research:

“During early development, apoptosis is needed to sculpt structures such as fingers and toes. Later on in life, apoptosis is also instrumental to ensure that organ size remains constant – a process called tissue homeostasis. For example, during each menstrual cycle the epithelium of the normal human breast undergoes a phase of cell expansion. However, later on, a phase of
cell removal follows which reduces the breast back to its original size. Similarly, during regnancy and lactation high levels of cell proliferation and differentiation occur in the breast, leading to a massive expansion of the mammary gland. But, after lactation has finished, the differentiated lactating lobules are no longer required and are then removed by apoptosis, returning the organ
to its mature resting state. Thus, during adult life, as during development, numerous structures are formed that are later removed by apoptosis.”

Very interesting isn’t it? Apoptosis plays a very important role in cancer.

“Substantial evidence indicates that the very same genetic mutations that trigger uncontrolled cell expansion, and hence might give rise to cancer, at the same time also trigger spontaneous activation of cell death. The finding that the molecular lesions that generate uncontrolled cell expansion also coordinately trigger cell death indicates that under normal circumstances apoptosis acts as a fail-safe strategy to hinder the expansion of potentially harmful cells. In
this respect, apoptosis acts as part of a quality-control and repair mechanism that eliminates unwanted cells. Consequently, cancer can only ever emerge if apoptosis has been suppressed.”

Below is the excerpt about cancer research done on the role of apoptosis in cancer:

“To try to resolve how cancer cells bypass apoptosis, the Apoptosis Team within The Breakthrough Toby Robins Breast Cancer Research Centre is studying the machinery that executes apoptosis and the molecular mechanisms that control this potentially catastrophic
process. Our work concentrates on the engines of the apoptotic execution programme. The destructive components of this cell-death machinery consist of a group of highly specialised proteases (enzymes that break down proteins) called caspases.

Caspases form the molecular chainsaws of the self-destruct programme which, when activated, cut the cell to pieces. Activation of caspases is a key event in apoptotic signalling and is required to execute cell death. Caspases are present in every cell at all times, but remain dormant. However, upon exposure to DNA damage, chemotherapeutic compounds or developmental signals, caspases become rapidly activated. Once active, caspases cleave and destroy a
multitude of polypeptides inside the cell that are vital for cellular function, shape and integrity. Cells are destroyed and removed within minutes of caspase activation – an event which is, self-evidently, potentially catastrophic and must be tightly regulated.”

Inhibitors of apoptosis (IAPs) function as guardians of the apoptotic machinery. Recent studies show that several human IAPs are strongly upregulated in many cancers. Since IAPs suppress apoptosis very effectively and are present in cancer cells, tumour pathogenesis occurs. This is also the cause of disease progression and resistance to drug treatments in cancer. Mark Ditzel and Rebecca Wilson have investigated how IAPs suppress cell death. They made the striking
observation that IAPs inhibit deadly caspases by fusing another protein, called ubiquitin, onto caspases. The ubiquitin label inactivates the caspases and the cancer cell survives. IAPs belong to a specialised group of proteins, called E3 ubiquitin protein ligases, which transfer ubiquitin
protein labels onto caspases thereby blocking cell death. It is now clear that apoptosis is implemented by caspases. To date 11 caspases have been identified in humans.While XIAP suppresses only three of these, it is currently unclear how the remaining set of caspases is controlled.

I’ve also read something very interesting. Read this too:

“Tencho Tenev and Anna Zachariou have studied how caspases are kept in abeyance. They made the discovery that certain caspases carry an evolutionarily conserved motif, which is designed to attract and bind to IAPs, hence the name IAP-binding motif (IBM). Normally, this
IBM is buried deep within a dormant, non-active caspase. However, when the caspase is activated, this motif is exposed and acts like a magnet for IAPs. Thus, even when caspases are activated this will not necessarily end in cell death, because IAPs can home in on active caspases and smother their destructive potential. The most exciting aspect of this discovery is that only a tiny motif, in fact, one single amino acid residue of the caspase, is crucially involved in anchoring it to IAPs. Mutation of this one residue completely abrogates the interaction between IAPs and caspases. Consequently, activated caspases become invisible for IAPs and therefore are unrestrained and free to cause mayhem.”

In the future:

Small molecule inhibitors already exist to block IAPs. Future studies will undoubtedly determine whether such SMAC compounds can be turned into efficacious small molecules that enhance the apoptotic mechanism, either alone or in combination with conventional hemotherapeutic agents.

I liked this article. Its taken from the annual research report 2004 from the Institute of Cancer Research website. http://www.icr.ac.uk.

Biological Background

Cancers are caused by a series of mutations. Each mutation alters the behavior of the cell somewhat.

Carcinogenesis, which means the initiation or generation of cancer, is the process of derangement of the rate of cell division due to damage to DNA. Cancer is, ultimately, a disease of genes. In order for cells to start dividing uncontrollably, genes which regulate cell growth must be damaged. Proto-oncogenes are genes which promote cell growth and mitosis, a process of cell division, and tumor suppressor genes discourage cell growth, or temporarily halt cell division in order to carry out DNA repair. Typically, a series of several mutations to these genes are required before a normal cell transforms into a cancer cell.

Proto-oncogenes promote cell growth through a variety of ways. Many can produce hormones, a “chemical messenger” between cells which encourage mitosis, the effect of which depends on the signal transduction of the receiving tissue or cells. Some are responsible for the signal transduction system and signal receptors in cells and tissues themselves, thus controlling the sensitivity to such hormones. They often produce mitogens, or are involved in transcription of DNA in protein synthesis, which creates the proteins and enzymes responsible for producing the products and biochemicals cells use and interact with.
Mutations in proto-oncogenes can modify their
expression and function, increasing the amount or activity of the product protein. When this happens, they become oncogenes, and thus cells have a higher chance to divide excessively and uncontrollably. The chance of cancer cannot be reduced by removing proto-oncogenes from the genome as they are critical for growth, repair and homeostasis of the body. It is only when they become mutated that the signals for growth become excessive.

Tumor suppressor genes code for anti-proliferation signals and proteins that suppress mitosis and cell growth. Generally tumor suppressors are transcription factors that are activated by cellular stress or DNA damage. Often DNA damage will cause the presence of free-floating genetic material as well as other signs, and will trigger enzymes and pathways which lead to the activation of tumor suppressor genes. The functions of such genes is to arrest the progression of cell cycle in order to carry out DNA repair, preventing mutations from being passed on to daughter cells. Canonical tumor suppressors include the p53 protein, which is a transcription factor activated by many cellular stressors including hypoxia and ultraviolet radiation damage.
However, a mutation can damage the tumor suppressor gene itself, or the signal pathway which activates it, “switching it off”. The invariable consequence of this is that DNA repair is hindered or inhibited: DNA damage accumulates without repair, inevitably leading to cancer.
In general, mutations in both types of genes are required for cancer to occur. For example, a mutation limited to one oncogene would be suppressed by normal mitosis control and tumor suppressor genes, which was first
hypothesised as the Knudson hypothesis. A mutation to only one tumor suppressor gene would not cause cancer either, due to the presence of many “backup” genes that duplicate its functions. It is only when enough proto-oncogenes have mutated into oncogenes, and enough tumor suppressor genes deactivated or damaged, that the signals for cell growth overwhelm the signals to regulate it, that cell growth quickly spirals out of control. Often, because these genes regulate the processes that prevent most damage to genes themselves, the rate of mutations increase as one gets older, because DNA damage forms a feedback loop.

Usually, oncogenes are dominant, as they contain gain-of-function mutations, while mutated tumor suppressors are recessive, as they contain loss-of-function mutations. Each cell has two copies of the same gene, one from each parent, and under most cases gain of function mutation in one copy of a particular proto-oncogene is enough to make that gene a true oncogene, while usually loss of function mutation needs to happen in both copies of a tumor suppressor gene to render that gene completely non-functional. However, cases exist in which one loss of function copy of a tumor suppressor gene can render the other copy non-functional. This phenomenon is called the dominant negative effect and is observed in many p53 mutations.

Mutation of tumor suppressor genes that are passed on to the next generation of not merely cells, but their offspring can cause increased likelihoods for cancers to be inherited. Members within these families have increased incidence and decreased latency of multiple tumors. The mode of inheritance of mutant tumor suppressors is that affected member inherits a defective copy from one parent, and a normal copy from another. Because mutations in tumor suppressers act in a recessive manner (note, however, there are exceptions), the loss of the normal copy creates the cancer phenotype. For instance, individuals who are heterozygous for p53 mutations are often victims of Li-Fraumeni syndrome, and those who are heterozygous for Rb mutations develop retinoblastoma. Similarly, mutations in the adenomatous polyposis coli gene are linked to adenopolyposis colon cancer, with thousands of polyps in colon while young, while mutations in BRCA1 and BRCA2 lead to early onset of breast cancer.

Cancer pathology is ultimately due to the accumulation of DNA mutations that negatively effect expression of tumour suppressor proteins or positivly effect the expression of proteins that drive the cell cycle. Substances that cause these mutations are known as mutagens, and mutagens that cause cancers are known as carcinogens. Particular substances have been linked to specific types of cancer. Tobacco smoking is associated with lung cancer. Prolonged exposure to radiation, particularly ultraviolet radiation from the sun, leads to melanoma and other skin malignancies. Breathing asbestos fibers is associated with mesothelioma. In more general terms, chemicals called mutagens and free radicals are known to cause mutations. Other types of mutations can be caused by chronic inflammation, as neutrophil granulocytes secrete free radicals that damage DNA. Chromosomal translocations, such as the Philadelphia chromosome, are a special type of mutation that involve exchanges between different chromosomes.
Many
mutagens are also carcinogens, but some carcinogens are not mutagens. Examples of carcinogens that are not mutagens include alcohol and estrogen. These are thought to promote cancers through their stimulating effect on the rate of cell mitosis. Faster rates of mitosis increasingly leave less opportunities for repair enzymes to repair damaged DNA during DNA replication, increasing the likelihood of a genetic mistake. A mistake made during mitosis can lead to the daughter cells receiving the wrong number of chromosomes, which leads to aneuploidy and may lead to cancer.

Furthermore, many cancers originate from a viral infection; this is especially true in animals such as birds, but less so in humans, as viruses are only responsible for 15% of human cancers. The mode of virally-induced tumors can be divided into two, acutely-transforming or slowly-transforming. In acutely transforming viruses, the viral particles carry a gene that encodes for an overactive oncogene called viral-oncogene (v-onc), and the infected cell is transformed as soon as v-onc is expressed. In contrast, in slowly-transforming viruses, the virus genome is inserted, especially as viral genome insertion is an obligatory part of retroviruses, near a proto-oncogene in the host genome. The viral promoter or other transcription regulation elements in turn cause overexpression of that proto-oncogene, which in turn induces uncontrolled cellular proliferation. Because viral genome insertion is not specific to proto-oncogenes and the chance of insertion near that proto-oncogene is low, slowly-transforming viruses have very long tumor latency compared to acutely-transforming viruses, which already carry the viral-oncogene.
It is impossible to tell the initial cause for any specific cancer. However, with the help of
molecular biological techniques, it is possible to characterize the mutations or chromosomal aberrations within a tumor, and rapid progress is being made in the field of predicting prognosis based on the spectrum of mutations in some cases. For example, some tumors have a defective p53 gene. This mutation is associated with poor prognosis, since those tumor cells are less likely to go into apoptosis or programmed cell death when damaged by therapy. Telomerase mutations remove additional barriers, extending the number of times a cell can divide. Other mutations enable the tumor to grow new blood vessels to provide more nutrients, or to metastasize, spreading to other parts of the body.

Malignant tumors cells have distinct properties:

evading apoptosis
unlimited growth potential (immortalitization) due to overabundance of
telomerase
self-sufficiency of
growth factors
insensitivity to anti-growth factors
increased
cell division rate
altered ability to
differentiate
no ability for
contact inhibition
ability to invade neighbouring
tissues
ability to build
metastases at distant sites
ability to promote blood vessel growth (
angiogenesis)

A cell that degenerates into a tumor cell does not usually acquire all these properties at once, but its descendant cells are selected to build them. This process is called clonal evolution. A first step in the development of a tumor cell is usually a small change in the DNA, often a point mutation, which leads to a genetic instability of the cell. The instability can increase to a point where the cell loses whole chromosomes, or has multiple copies of several. Also, the DNA methylation pattern of the cell changes, activating and deactivating genes without the usual regulation. Cells that divide at a high rate, such as epithelials, show a higher risk of becoming tumor cells than those which divide less, for example neurons.

Signs and symptoms

Roughly, cancer symptoms can be divided into three groups:

Local symptoms: unusual lumps or swelling (tumor), hemorrhage (bleeding), pain and/or ulceration. Compression of surrounding tissues may cause symptoms such as jaundice.

Symptoms of metastasis (spreading): enlarged lymph nodes, cough and hemoptysis, hepatomegaly (enlarged liver), bone pain, fracture of affected bones and neurological symptoms. Although advanced cancer may cause pain, it is often not the first symptom.

Systemic symptoms: weight loss, poor appetite and cachexia (wasting), excessive sweating (night sweats), anemia and specific paraneoplastic phenomena, i.e. specific conditions that are due to an active cancer, such as thrombosis or hormonal changes.

Every single item in the above list can be caused by a variety of conditions (a list of which is referred to as the differential diagnosis). Cancer may be a common or uncommon cause of each item.

A Little Intro to Cancer

Childhood cancers

Cancer can also occur in young children and adolescents, but it is rare. Pediatric cancers, especially leukemia, are on an upward trend. Though some studies have not shown this, others done over a longer scale of time have so indicated.

The age of peak incidence of cancer in children occurs during the first year of life. Leukemia (usually ALL) is the most common infant malignancy (30%), followed by the central nervous system cancers and neuroblastoma. The remainder consists of Wilms’ tumor, lymphomas, rhabdomyosarcoma (arising from muscle), retinoblastoma, osteosarcoma and Ewing’s sarcoma.

Female and male infants have essentially the same overall cancer incidence rates, but white infants have substantially higher cancer rates than black infants for most cancer types. Relative survival for infants is very good for neuroblastoma, Wilms’ tumor and retinoblastoma, and fairly good (80%) for leukemia, but not for most other types of cancer.

Origins of cancer

Cell division or cell proliferation is a physiological process that occurs in almost all tissues and under many circumstances. Normally the balance between proliferation and programmed cell death is tightly regulated to ensure the integrity of organs and tissues. Mutations in DNA that lead to cancer disrupt these orderly processes.

The uncontrolled and often rapid proliferation of cells can lead to either a benign tumor or a malignant tumor (cancer). Benign tumors do not spread to other parts of the body or invade other tissues, and they are rarely a threat to life unless they extrinsically compress vital structures. Malignant tumors can invade other organs, spread to distant locations (metastasize) and become life-threatening.