We’ll start out with a few definitions regarding tumors:
Integrin-cell surface proteins which interact with the extracellular matrix
Angiogenesis-the branching and growth of new blood vessels by growth of new branches.
CXC chemokine-small proteins (CXCL4 has 70 residues) which play a role in chemotaxis
Specific proteins to know:
α5β1-fibronectin receptor; also plays a role in angiogenesis
CXCL4-an αvβ3 antagonist found in platelets and plays a role in neutralizing heparin like molecules thereby enhancing coagulation
Now for some basics on cancer.
As tumors grow, they require more and more nutrients to feed the mass of cells. To accomplish this, they rely upon angiogenic factors to trigger growth of new blood vessels bringing oxygen and nutrients. Metastasis is one way tumors spread. This involves the migration of a cancerous cell into the blood stream and moving to another location and invading the surrounding tissue further downstream by use of integrin proteins. By stopping cancer from producing blood vessels and spreading, we can isolate tumors to very small masses in isolated locations making them far easier to treat with very specific radiation levels in very specific locations.
But first, we must prevent metastasis and angiogenesis.
Nucleolin is a potential target for tumor treatment for a number of reasons. Chief among these is the fact that nucleolin plays a role in angiogenesis, and as previously stated, without angiogenesis or metastasis, tumors cannot exceed a very small size. The researchers here used an antagonist to cell surface nucleolin (HB-19 and anti-nucleolin monoclonal antibody (mAb) which, while not resulting in disruption of normal cell metabolism and behavior, resulted in marked decreases in tumor proliferation. Another observation was that a marked decrease in cells at S phase was observed. This is consistent with the expected decrease in replication of cells via prevention of DNA replication.
Now for angiogenesis. The researchers in this paper looked at VEGF stimulated HUVECs (“vascular endothelial growth factor” and “human umbilical vein endothelial cells” respectively) . When VEGF or PTN (pleiotrophin) were used, HB-19 and anti-nucleolin mAb (monoclonal antibody) had very similar inhibition of vascular formation. When FGF-2 (basic fibroblastic growth factor) was used, HB-19 (a drug being tested) had a much higher efficacy than anti-nucleolin mAb at decreasing angiogenesis.
They then had some fun torturing poor little athymic nude mice. They injected human breast carcinoma cells (that proliferate when untreated into palpable tumors in two weeks) into them. Following this, they began treatment with tamoxifen in some mice and HB-19 in others. Autopsy revealed no side apparent side effects compared to control mice injected with phosphate buffer solution (PBS) alone. The HB-19 treated mice also exhibited no side effects such as diarrhea, infection, weakness, lethargy, blood cell counts, or body weight. Mice treated with HB-19 also exhitibted some elimination of measurable tumors. HB-19 was also more efficient at treating tumors than tamoxifen in higher dose levels! Now, HB-19 was not as effective as 5-FU, however 5-FU has significant side effects on lymphocyte counts.
So, what does this mean? Well, firstly, HB-19 may make a very good auxiliary treatment for tumors. It may allow chemotherapy to be in much lower doses and far less frequently. This is one possible route for tumor treatment presented by this specific research.
So here we go:
I’m going to start out with a little info on CXCL4, also known as PF4. CXCL4 is fairly small, only 70 residues, protein and looks something like this.
It binds to several integrins (αvβ3, αvβ5, and α5β1) and by these integrin interactions, inhibits angiogenesis to some degree. Unlike HB-19, CXCL4 does not invade the cell, but functions as a surface signal. CXCL4 blocks endothelial cell migration in response to VEGF and FGF, and as a result, prevents angiogenesis. The precise mechanism of this is not yet known, although it is likely similar to contortrostatin.
It is also interesting to note exactly how many things αvβ3 actually binds to.
Lastly: Erythropoietin (EPO) blockade
Recombinant EPO therapy is commonly used after chemotherapy to replenish red blood cells, but this has been implicated in making recurrence of tumors far more likely. These researchers decided to look at what EPO actually does with regard to tumors and angiogenesis and the results were pretty interesting.
Studies previously looked at systemic and short term EPO treatments to determine effects of EPO on turmors while this study involved high concentrations of EPO in the tumor microenvironment.
Now, this is interesting, but doesn’t really give any good treatment options. It does do something, however. It tells us how NOT to treat after chemotherapy. We should NOT give high doses of rEPO to patients after receiving radiation or chemo.
I’m going to conclude here by saying these three papers I covered (two of them only very briefly) are part of the rapidly growing body of knowledge relating to cancer formation, growth, and progression which are helping to combat this devastating group of highly prolific cells.