CANCER DIARY OF OSTEOSARCOMA SUBMITTED BY

CANCER DIARY OF OSTEOSARCOMA
SUBMITTED BY: ARAGAW GEBEYEHU
SUBMITTED: DR. FLORES ROZAS
DATE OF SUBMISSION: 04/16/18
01/26/12
My name is osteosarcoma. I am a highly malignant tumor of mesenchymal origin and the second most common primary malignant bone tumor.I originate from mesenchymal cells. I have spindle shape and hyperchromatic nucleus. I have been formed when osteoblasts cells secreted malignant osteoid. I am like osteoblast (bone forming) cells, but I cannot make a strong matrix like them. You know that osteoblasts originate from immature mesenchymal stem cells. So my ancestors are from those. But I am already modified into osteosarcoma cell. I can occur at any bones found in the body. I am more frequent at sites of the most rapid bone growth; those are extremities of long bones near metaphyseal growth plates. From the sites that I frequently choose; distal and proximal end of a femur (42%), a proximal end of the tibia(19%), the proximal end of the humerus (10%), pelvis skull and jaw(85%) and pelvis( 8%). I can be appearing 1 to 3 million people per year. Of course, I am rare compared to other types of cancer. I can attack any age as primary osteosarcoma but mostly between 10-25yrs. I can also come at older individuals as secondary osteosarcoma. I affect males little bit more than females. I am most common in patients with Fraumeni syndrome, Rothmund-Thomson syndrome, Bloom and Werner syndromes. Exposing to Paget disease and ionizing radiation give favorable conditions for me to develop our colony.

Fig 1. Osteosarcoma genesis and osteogenesis

When I was changing to osteosarcoma, there was a mutation of MDM2 amplifications which led to p53 gene inactivation. Another controller gen which is called retinoblastoma (RB) genes was also altered. I become safe because there is no more checkpoint and control for me.But the normal bone cells have several checkpoints in their cell cycle. In the presence of RB mutations, I will occur at an incidence 500 times that of the normal population. Normal cells are always worrying
about G1/S checkpoint but I am not, because the p53 and Rb genes are already mutated (lost their function). I am preparing more DNA and for that I am also synthesizing mRNA and important proteins. During my replication time, I gained chromosome number 1 and lost chromosome 9, 10 and 13. Till now I am successfully dividing and I am forming other similar cells. In near future, I will have my own colony of cells and my own sarcoma tissues
01//14/2014
As usual, I was preparing to divide but the proteins detected a damage in my DNA. The damage was too big to be repaired. Even if it is bigger damage I will not go to programmed cell death called apoptosis. Because this is not my character. My only goal is to survive and proliferate more. This is my unique behavior. Of course, I was not like this, I was following the normal path of the cell cycle and programmed cell death. This thing happened after I lost my DNA sequence that triggers cell death pathway.

5/18/15
Recently I got other mutations and my FOS and Jun proteins are up-regulated. Those proteins are components of activator protein1 complex (AP-1).AP-1 his regulator of cell transcription. Now I am getting additional energy because my transcription regulators are out of service. I can proliferate freely and destroy bone cortex and extend towards bone marrow cavity and soon outwards towards adjacent soft tissues.

10/17/15
I am now thinking why not I visit other organs. I have information lung, liver and also other bones are the safe place and more fertile to me.when I become more organized, I can migrate and live there. I am already resistant to programmed cell death (anoikis) and can exhibit anchorage-independent growth (AIG). Abnormal integrin? ??v6, Rho, ATPase e.g. Racl and Cdc42 upregulated p13 kinases which in turn inhibited proapoptotic factor Bad and this protected me from apoptosis even when I am not attached to any membrane. Now I have bigger size with the hypoxic and acidic environment. So I need supporting blood vessels to obtain oxygen and nutrients I have done angiogenesis for my sustained growth and further metastasis. My intrinsic conditions have to lead to stimulation of von Hippie Lindau protein. It releases hypoxia-inducible factor-1? (HIF-?)which further up-regulates several VEGF gene such as VEGF A through VEGF E. This further releases Nitric oxide (NO) from endothelial cells and results in vasodilation and increased vascular permeability. By doing those processes I got leaky and irregular vasculature.

3/14/16
I am starting a flight to the lung. I am using integrin proteins, which found on my surface, in attaching to matrix proteins (fibronectin).For my signal transduction and interaction with other cells, I use integrin along with ezrin protein, foal adhesion kinase (FAK), protein kinase C (PKC) and Rho GTPase. They also help me with my conformational changes. Besides to this matrix metalloproteinase (MMPs) are helping me in my sojourn through blood vessels and tissue renewal process. Now I have reached the lungs and I am growing, multiplying and consuming all nutrients. It is like as I heard.I like it.
10/10/2016
Today, the patient could not resist me.He took me to hospital. Because I create severe pain and swelling. I was diagnosed with radiograph as high-grade sarcoma. Additionally, they did CT scan, RI, and biopsy and confirmed my stage. They are now discussing to fight against me.Yes, they have started chemotherapy (high dose methotrexate, doxorubicin, and cisplatin).i have been fighting against those drugs for the last three months and I am now getting old, starving and feeling weaker day by day. Oh,, those drugs become treble for me. Methotrexate is a dihydrofolate reductase inhibitor, it can block folic acid supply which is needed for my RNA and DNA synthesis. Doxorubicin which is also a drug that interacts with my DNA and inhibits biosynthesis of macromolecules. Cisplatin causes damage to my DNA. I have to create solutions because I am no longer able to make RNA efficiently. But I am struggling to continue my life. I got another mutation which is an alteration of reduced folate reductase (RFC) protein Leu291pro. This alteration unable carrier to transport methotrexate towards me.Besides to this, membrane pump-glycoproteins (P-gp) is also helping me with pumping out these drugs. Due to this, I start dividing and spreading slowly but steadily. Other worse situations are happening to me, they are using high energy rays (x-rays) to kill me. I am no longer able to grow. I am shrinking.

4/14/18
The worst thing has happened to me. Now, they are performing surgery and removing me as cancerous tissue. I was sending my daughters to afar to the lung. By myself, I am highly depressed and weak due to huge loss my colony. I try to grow and spread again by my reserve soldiers and by those immigrant members. They are still in dilemma to administer chemotherapeutic agent after surgery. The people are always struggling to combat me and other friends. If they post-surgery chemotherapy no more survival .I say goodbye I will not be there anymore.

REFERENCE
Biomarkers in osteosarcoma, Colin Kong, M.S and Marc F. Hansen, Ph.D.

Biology and therapeutic advances in pedia
tric osteosarcoma, Nayssa Marina Et.al,The oncologist ,2003
Novel therapeutic strategy for osteosarcoma targeting osteoclast differenciation, bone reabsorbing activity , and apoptosis pathways.

The molecular pathogenesis of Osteosarcoma; A review, Matthew L. broadhead, sarcoma, 2011.

Current strategy for chemotherapy in Osteosarcoma, Dorothy carric, International Orthopedics, 2006
Osteosarcoma: A review of diagnosis, management and treatment strategies, David S. geller , MD, and Richard Gorlic MD
Switch from ?v?5 to ?v?6 integrin expression protects squamous cell carcinomas from anoikis, S.M. Janes, Journal of cell Biology,2006.

Analysis of molecular mechanisms of osteosarcoma using bioinformatics approach, Jaxon yang ,oncology letters,2016.