Blood, yellow bile, black bile and phlegm are the four bodily fluids according to humoral theory. I think three of them are obvious to us as they help in maintaining body's physiological homeostasis. But what is that black bile responsible for? People in the early century thought that this black bile was responsible for something that causes the death of millions of people in the world today, cancer.
What is Cancer?
Cancer is a melancholic situation in which our body cells divide and proliferate rapidly. This doesn't sound too disturbing right? Just a bunch of cells dividing and creating more copies. But still millions of people die of it every year and no one has the cure of cancer. And that is the point. Although it appears pretty straightforward, it definitely isn't. And that very 'Intricacy in the simplicity' is for me the most characteristic feature of cancer.
Cancer cells are abnormal cells that divide and proliferate in our body. Cancer cells are of two types; benign and malignant. Benign and malignant cancer cells are almost similar except for one important property that the benign cancers aren't metastatic. Metastasis meaning invading other parts, moving away from the cancer origin. Benign cancers can be cured but malignant cancers are very difficult to be cured, certainly not impossible. A small tumor can posses metastasis intrinsically while a large tumor can be be benign. Predicting the tumor's future bases on size is not always accurate.
Historical advancement in cancer therapy
Cancer is not a new disease. The earliest cancerous growth in humans were found in Egyptian and Peruvian mummies dating back to 1500 BC. People in the earlier times died more of epidemics like plagues, Spanish flu, TB etc. People in those time didn't live long enough to be dead by cancer as cancer is a age related disease. People died too soon. In 1800s chimney sweepers people recorded scrotal cancer.
Sidney Farber was a pathologist whose main task was performing post mortem of bodies. Sidney became a full time pathologists at the Children's Hospital in Boston in 1929. His lab was in the basement of the building. Later in his career he encountered a lot of child death due to leukemia(blood cancer). At that time in mid 1900s, cancer biology was not a profound subject. So he committed himself in the battle with cancer. After some work he postulated that folic acid, which was responsible for normal cell division was the key factor that led cancer cells divide haphazardly. He then used an anti folate, aminopterin to suppress cancer. He then conducted trial with aminopterin and got success, temporarily. Together with the Variety Club of England in 1947, he established the Children's Cancer Research Foundation(CCRF). Throughout the 1950s and '60s, he continued to make advances in cancer research, notably the 1955 discovery of antibiotic actinomycin D and radiation therapy could produce remission in Wilm's tumor. Together with Mary Lasker, Farber founded Jimmy fund in 1948. The campaign of Jimmy fund turned out to be one of the biggest campaign in medical science history collecting millions of dollars to fund for cancer research. With the help of Lasker, Farber led the drive for a massive expansion in federal spending for cancer research. Many drugs were introduced in the mid '90s and the idea of radical surgery, adjuvant therapy, X ray treatment were starting to be profound. Several large scale trial were conducted and many of them showed good results. But in 1986 Bailar and Smith published an article in May 1986 which showed cancer related deaths had increased by 8.7% instead of decreasing between 1962-1985 despite all the developments and progress in cancer medicine. Between 1957 and 1967, the annual budget of the National Cancer Institute jumped from $48 million to $176 million. In 1983, Farber's CCRF together with Dana's foundation was renamed to Dana-Farber Cancer Institute in 1983. Between 1990 and 2005, cancer specific death rate dropped by 15% and breast cancer by 24%. Unfortunately, Farber died of cancer in 1973. He is now known as the father of modern chemotherapy.
Chemotherapy
Chemotherapy is the use of drugs to treat cancer. A combination of drugs is used instead of single drug because the cancer cells develop resistance to that single drug over time. One such drug combination goes by the name VAMP which stands for Vincristine, Adriamycin, Mercaptopurine and Prednisone. VAMP was used as a chemotherapeutic agent against Hodgkin's Lymphoma. Cisplatin was a widely used drugs for cancer treatment in late 90's . Paraplatin, Docetaxel, Platinol, Avastin, Borteomib, Revlimid, Taxol, Gleevec, Cyclophosphamide are some of the names of the chemo drugs. An important drug for breast cancer is Herceptin. Generally chemotherapy is followed by surgery. During surgery the lump of cancerous tissue is removed but to make sure that the patient is fully free of cancer, drugs are used to obliterate extra scattered cancerous cells. For Estrogen related cancer, an anti estrogenic drug Tamoxifen is used. But these drugs have side effects. When Cisplatin was used to treat cancer, the patient was seen to vomit nearly 12 times a day. Bone marrow is very sensitive to drugs. If used above limit, bone marrow gets damaged and new cells won't be formed. In fact high doses of drugs damages bone marrow so severely that it causes myelodysplasia, a condition that tends to progress to leukemia. The leukemia that arises from chemotherapy treated marrow would be virtually resistance to any drugs.
Carcinogenesis
Cancer biologists admit that they don't fully understand cancer biology. It is one of the reasons that this disease is so hard to cure. But, we all know that cancer is genetic. Parents with cancer have a higher chance that their offspring also inherit the disease. Now let's dive into whatever we know about carcinogenesis.
We humans have 23 pairs of chromosomes. The chromosomes contain many genes. Not only genes but oncogenes(cancer causing genes). Yes, we carry oncogenes within us. A cancer cell has about 20 thousand genes. There are many oncogenes just waiting to cause cancer. There are two types of genes. First, positive gene that accelerates cell division and next is suppressor gene, which must be inactivated to develop cancer. But, if we carry so many oncogenes why don't we all get cancer immediately?
It is because
- These oncogenes need to be activated through mutations and mutations are rare events. Also mutations need to happen multiple times .
- Cancer is slow and long process.
- Suppressor genes need to be inactivated in both copies of chromosome.
The genes encode protein. The oncogene encodes protein that modifies other protein by attaching a phosphate group. These genes are kinases. Human genome has about 500 kinases. The modified protein modifies another protein and in a cascade manner many protein are modified that causes cell to divide malignantly. Gene act in signaling pathway. Ras protein activates Mek, mek activates Erk and it accelerates cell division. So to sum up, the oncogenes get mutated which modifies protein in a cascading manner resulting in abnormal proliferation of cell. The tumor suppressor genes need to be inactivated in both genes to cause cancer and it is inactivated by adding phosphate group. Some examples of oncogenes are myc, neu, fos, ret, ras, src. BRCA-1 is one of the most common caner linked genes found in humans. We know that soot, radiation, UV rays, virus also cause cancer but the mechanism is same. It is believed that every patient's cancer possess it's own unique sequence of gene mutation but it is found that cancer do not activate or inactivate genes at random. There is a strict and stereotypical sequence.
Cancer also occurs due to chromosomal aberrations like Chronic Myeloid Leukemia(CML) caused by gene Ber-abl due to translocation between chromosome 22 and 9 but the mechanism is same as above. There are hormone dependent cancers too. Prostate cancer cells require testosterone. In breast cancer, the "ER positive" breast cancer, depleting estrogen shrinks the tumor.
Why is cancer almost incurable?
Cancer is 'The Emperor of all Maladies' as Siddhartha Mukherjee calls it. Here are some answers to that question :
- Cancer cells are not much different from normal cells. When bacteria or viruses attack us, their cell or enzymatic products are very different from host body, in this case ours. So the drugs can't be specifically prepared for cancer cells because a drug can fails to recognize normal and cancerous. So drugs kill our healthy cells too.
- Even if the drugs killed cancer cells, over the period of time the genes mutate and the drug resistant cancer cell grows back. Cancer cells even become resistant to a combination of drugs. Then, second generations drugs must be developed and the battle never ends.
- Many cancer aren't detected in early stages. Once it metastasize, it is almost unstoppable. It eats you inside.
- Leukemia cells colonizes the brain and even the highly potent drugs don't cross the blood brain barrier. So cancer affecting brain is very very hard to overcome.
- Surgeries, X ray treatment and chemo are costly and it can't be afforded by ordinary people. Also if chemo and x rays are above limit, it again causes cancer. Treatment of cancer can further cause the disease, what an irony.
- We cannot manipulate mutations. They occur rarely so there is no way to predict them.
- Incomplete understanding of cancer genetics, cancer biology and carcinogenesis is a major reason. As San Tzu has written in his book 'The Art of war' if you haven't understood your enemy, you're most certainly not winning the war.
- The ability of the cancer cell to divide immortally is not understood. It multiplies generations with high vigor.
Future predictions
It is difficult to make future predictions. But, if you ask any oncologist about what has changed between 1990 and 2023 in cancer biology then there is an universal answer, 'We are making progress'. I think we still need to have a better grasp of cancer biology, we have to understand our enemy. With the likes of gene editing technology, maybe we are closer to cancer cure but only the time will tell. A better option for early cancer diagnosis is a must, in my opinion. But I think this is a never ending battle. We have to keep improvising and keep reinventing our knowledge, technology to have a upper hand in this battle. More people being interested in cancer therapy is always a good thing but I think we need a bit or more than that if we want to win our battle against 'The Emperor of all Maladies'
* I will leave you with an interesting fact which is that dogs, humans and lions are the only animals that develop prostate cancer. Elderly people die with prostate cancer then die of prostate cancer.
This blog is motivated by Dr. Siddharth Mukherjee's Pulitzer prize winning book 'The Emperor of all Maladies'. I highly recommend this book for anyone who wants to dive into the world of cancer.
You can contact me at :- kafleashesh24@gmail.com
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