This week of my course is devoted entirely to cancer. The previous week was devoted entirely to inflammation. Combined, these two weeks make up the translation portion of our cell biology and genetics course, Block 2. Translation is a big buzz word, especially here at Cornell where the dean of the veterinary school is a researcher (_not_ a clinician at all mind you!) keen on translational research (which is essentially applied research-- or applying research to come up with better treatments for clinical problems). My experience as a patient at UCSF had already convinced me of the power of 'bench-t0-bedside' medicine long before I arrived at Cornell. My doctors there implemented the latest research in treating me, and were not only skilled surgeons and diagnosticians, but good researchers, or at the very least well educated on the most recent breakthroughs in their field.
I've had a few epiphanies during this week, I am beginning to understand the basics of cancer. For one thing, cancer comes about because of mutations in stem cells or other progenitor-type cells capable of proliferation. I never really understood this before. Non-stem cells/non-progenitor cells do not have the limitless replicative potential necessary for cancerous growth, which is one of six hallmarks of cancer (the other five are-- sustained angiogenesis, evading apoptosis/programmed cell death, self-sufficiency in growth signals, insensitivity to anti-growth signals, tissue invasion and metastasis).
Furthermore, the mutations that occur are usually in growth regulatory genes, typically oncogenes or tumor repressor genes. My professor, Dr. Levine, defines an oncogene as 'an altered gene whose product can act to help make a cell cancerous. It is generally a positive regulator of cell proliferation and is dominant... Mutations that activate proto-oncogenes are dominant, gain-of-function mutations, in which the oncoprotein is no longer tightly regulated.' The mutation does not have to be in the coding region of the gene itself, simple over-expression of a normal pro-proliferation cellular gene can turn it into an oncogene!
Chronic proliferation is a risk factor for cancer because every time a stem cell divides it is at risk for acquiring mutations that predispose it to cancer. I say mutations-- plural-- because in order to become cancerous, a cell must acquire multiple mutations since there are multiple characteristics/strategies/traits that are necessary for malignant cell growth and one mutation will not meet all the criterion needed to produce a cancer cell (see above for the six hallmarks of cancer). The need for multiple mutations helps explain why there is often a long latency period between exposure to a carcinogen and the development of cancer. It also is one reason that the risk for cancer is increased in older individuals-- they have had more time to accumulate mutations.
Here are some things that now make more sense to me-- you are more at risk for developing cancer under a scar than in unblemished skin (why is that? in order to heal and form a scar, the stem cells in that area were forced to divide, predisposing them to developing malignant mutations). The slide in my notes that says, 'The prevalence of growth disturbances depends on capacity of cells to reproduce' makes sense for the same reason. Most cancers originate from continuously replicating cells such as epidermis, GI tract epithelium and immune system cells. Some cancers come from stable cells that do not typically replicate but possess the ability to regenerate, i.e. liver/hepatocytes. Cells that have very little regenerative cancer like cardiac myocytes and neurons rarely become cancerous because they don't have stem cells that divide frequently (or at all in some cases).
My understanding of the importance of the role of proliferation in cancer also allowed me to understand aspects of my lecture on viral oncogenesis. Bovine leukemia virus is non-transducing long latency retrovirus that causes lymphocytosis (an increased number of lymphocytes) in about a third of cows one year after infection (technically this is leukemia but cows are hardy animals and don't show any clinical signs of disease unlike many other species). 5% develop bovine lymphosarcoma after 8 years. The tumors do not show viral expression and there is no viral oncogene activated by integration of bovine leukemia virus. The cancer stems from accumulated mutations due to the increased rate of replication of the lymphocytes.
Right now I'm studying pathology, how one identifies a malignant neoplasm. It turns out that it is not that easy! The three major differentials for a swelling/tumor are neoplasia (benign or malignant), inflammation and hyperplasia. Hyperplasia is defined in my notes as an increase in size due to an increase in the number of cells. It can be a protective response that regresses completely or it can go on to become cancer. As if that isn't complicated enough, there is no _one_ criterion for distinguishing benign neoplasias from malignant neoplasias. Malignant neoplasias are, according to my pathology notes, typically infiltrative, destructive, anaplastic (i.e. poorly differentiated), mitotically active, rapidly growing sometimes with necrosis, may have a desmoplastic response (lots of immature fibrous connective tissue) and the only dead ringer (no pun intended) is metastasis. The characteristics of a malignant cells' morphology are cellular pleomorphism-- anisocytosis, anisokaryosis, increased number of nucleoli and loss of nuclear polarity. Beyond identifying a tumor as cancerous, one is also expected to differentiate it based on the type of tissue it is derived from (as well as the actual structure or organ). Epithelial-derived tumors have polygonal cells and are called carcinomas (or adenocarcinoma if they are derived from glandular epithelial tissue). Mesenchymal-derived tumors are spindle shaped or round cells, may form rafts/streams and are called sarcomas.
And then there are all the details that make veterinary medicine so very fun and challenging. For example-- the area of a lymph node that is first colonized by metastatic cancer cells is the subscapular sinus, except in pigs and dolphins. (Right, got that!)
I have yet to study several lectures I've had recently-- 1. on cancer and immunology (trying to use the immune system to combat cancer-- mostly how to activate cytotoxic T cells with pathogen molecular associated pattern molecules but also a bit on DNA vaccines), 2. a very dense lecture on angiogenesis, invasiveness and metastasis that went into specific homing/anchorage factors such as the chemokine receptor CXCR4 which is involved in bone metastases (and is only one of several molecules that make up the bone-metastatic signature), 3. tumor suppressor genes, 4. oncogenes, 5. understanding cancer risk and management which includes risk factors for animal cancers (number of estrus cycles before spay and breast cancer in dogs, age at spay and breast cancer in cats, uv exposure, lack of pigmentation (white fur color) and squamous cell carcinoma of the skin in dogs and cats, herbicide and lymphoma in dogs, second hand smoke and lymphoma in cats-- this is interesting, they think the correlation is meaningful because cats groom so they ingest the particulate matter of second hand smoke and expose their GI tract to those carcinogenic molecules).
And that's not counting the lectures I have yet to get tomorrow on cancer imaging and cancer therapy.
If I had more time I'd write about Philadelphia chromosome for my mom (maybe another night, or perhaps it will be a dinner discussion next week). Cancer is fascinating and fun as long as you aren't the one who has it. Or your pet. It's the leading cause of death overall in dogs-- regardless of age 1 in 4 dogs dies of cancer.
As for the vocabulary-- I ran out of time. But try this-- telangiectasias means veins appearing on the eyes and skin (Ataxia Telangiectasia is a human disease that is linked to high rates of cancer). And pathology is always good for a few terms-- agenesis, aplasia, metaplasia, dysplasia, anaplasia (and I'm purposefully leaving out all the obvious -plasias like hyperplasia and hypoplasia). My favorite for the night-- papillary, used to describe patterns formed by tumor cells, means pertaining to or resembling a nipple or forming a rounded mass.
Note-- if you made it all the way to the end of this post kudos to you. Sorry it is so incredibly long, just didn't have time to condense it to something less wordy.
Here's a poem I jotted down this afternoon while running errands, inspired by the recent sunshine and brilliant sunrise. It's a work in progress.
