ewinter's blog

From google maps, it is evident that the interspecific interaction documented in Figure 2 is approximately 10 feet to the left of the interspecific interaction documented in Figure 1.  In order to create these pictures, the physical position of the camera in space must have been different. This also explains the difference in backgrounds between Figure 1 - A and Figure 2 - A as well as Figure 1 - B and Figure 2 - B.  The background difference between Figure 1 - C and Figure 2 - C is due to both the position of the camera being different, but also the angle of the camera. The camera that took the picture that comprises Figure 2 - C must have been facing downward because of the snow on the ground.  In Figure 1 - C, the camera was parallel to the ground because the background is the LSL wall. The level of visual detail that may be discerned about the organism from the individual organism pictures differs between the two figures. This is due to the distance of the camera lens from the organism differing.  The distance of the camera from the organism was specified in the methods.

One possible area of therapeutic intervention suggested by McAllister and Weinberg would be inhibition of the intercellular signaling that ultimately leads to metastasis.  Small molecule inhibitors or neutralizing antibodies are what McAllister and Weinberg propose as options.  The authors mention that instigation into the clinical use of haematopoietic growth factors such as G-CSF, which is known to recruit pro-tumorigenic bone marrow cells, is ongoing.  Thus far, the clinical justification for this type of treatment seems dubious due to the pro-tumorigenic role of G-CSF.  Anti-angiogenic therapies have been improved and continue to be researched. 

Bone marrow derived cells are cells that originate from the bone marrow.  Cancer cells can release chemical signals that, upon reception by bone marrow derived cells, may recruit these cells as pro-tumor factors that help tumor growth and metastasis.  A crucial step to tumor metastasis is angiogenesis.  Once a tumor gains access to the blood stream, it can shed cells into circulation and they can implant in other places in the body and start new tumors.  One example cited by McAllister and Weinberg is that in mouse models of melanoma, lymphoma, lung carcinoma, and mammary carcinoma, the secretion by tumors of the inflammatory cytokine granulocyte-colony stimulating factor (G-CSF) recruits pro-tumor cells from the bone marrow into the blood stream.  It was also found that these bone marrow cells had distinct sets of genes that promote angiogenesis.  Another study cited by McAllister and Weinberg showed that the secretion of osteopontin by tumor cells induced pro-tumorigenic function in bone marrow cells by recruiting them to the tumor microenvironment.  The secretion of growth factors such as vascular endothelial growth factor-A by tumor cells also recruits bone marrow derived cells to the tumor microenvironment and elicits pro-tumorigenic function that aids in angiogenesis. 

Fibroblasts, generally, are cells that synthesize extracellular matrix and collagen, thereby providing the structure for animal tissues.  Cancer associated fibroblasts (CAFs) are often present in the tumor microenvironment and have been implicated in angiogenesis.  The authors cite a study in which CAFs released CXCL12 into the bloodstream in a breast tumor xenograft model.  CXCL12 can recruit bone marrow derived cells to the tumor microenvironment. 

Pre-metastatic niches are essentially pre-determined cites that have no implanted tumor cells yet, but have been tagged with markers that will allow tumor cell localization and metastasis.  A study cited by McAllister and Weinberg showed that tumor-derived VEFG-A and P1GF could recruit bone marrow cells not only to the tumor sites, but also to the lungs, which in this case was tumor free at that point but later gained tumor cells.  Upon implementation of these bone marrow derived cells, the lung fibroblasts upregulated expression of fibronectin, thereby recruiting more bone marrow cells. 

The tumor microenvironment is the cellular environment in which the tumor exists.  Tumors often undergo a process called angiogenesis.  This is when the tumor causes the formation of a new blood vessel so it can get its nutrients.  Furthermore, tumors that have access to a blood vessel may shed cells to be carried in the blood, then implant somewhere else to begin growth of another tumor.  This process is known as metastasis.  Tumors cause angiogenesis by secreting signaling molecules such as the growth factors bFGF and VEGF, as well as proteins.  The secretion of these also allows the tumor to avoid eliciting an immune response.  Other cells involved in the tumor microenvironment include fibroblasts - cells that synthesizes collagen which provides the structural framework for animal tissues and plays a role in wound healing.  Additionally, cancer of the bone includes bone marrow in its tumor microenvironment.

P53 has been the direct target of many potential treatments over the years.  The drug Gendicine delivers wild type p53 on an adenoviral vector, and was approved by the China Food and Drug Administration for the treatment of ovarian cancer (Ayen, 2018).  Advexin, a similar drug, was blocked by the FDA in 2008 for reasons that were not officially disclosed (Osborne, 2008). However, it is known that adequate therapeutic effects for trials involving adenoviral delivery of p53 did not exist (Zeimet, 2003).  One logical explanation for this is that p53 is quite upstream in the apoptosis pathway, leaving lots of room for downstream over-amplifications or mutations that allow the tumor to evade apoptosis. There are several ongoing clinical trials in which the p53 gene is inserted via an adenoviral vector (Ayen et al. 2018).  These clinical trials represent the revitalization of p53 based gene therapy, after it was concluded to have failed over a decade ago (Zeimet, 2003).

Similarly, PARP proteins (poly (ADP-ribose) polymerase) proteins are involved in multiple DNA repair processes and have been targeted through inhibition for the treatment of ovarian cancer. The PARP inhibitors that have been approved by the FDA have been shown to prevent breaks in single-stranded DNA (which have been affected by the BRCA mutation causing the onset of cancer) so that the enzyme PAR encourages the mitochondrial release of AIF; therefore leading to apoptosis of the cells affected by the cancer mutations. This therapy has been hypothesized to be combined with Bcl-2 inhibition, which is a family of proteins involved in regulating apoptotic pathways. The therapy hypothesized therapy focuses on PARP inhibition in conjunction with the increased inhibition of anti-apoptotic proteins from the Bcl-2 family, specifically BH3. The Bcl-2 inhibition therapy currently under clinical trial is the ABT-263 monotherapy, and has shown clinically significant results in competing with BH3 proteins for binding with anti-apoptotic proteins and preventing those proteins from inactivating pro-apoptotic proteins. In vitro, the combined therapy displayed increased caspase activity and encouraged the Bax/Bak apoptosis pathway (Yokohama, 2017).

Anti-apoptotic Bcl-2 family proteins have been the subject and target of multiple ovarian cancer therapies. BH3 mimetics, small molecule inhibitors, have been designed over the years for the inhibition of anti-apoptotic proteins in an effort to induce apoptosis of cancer cells. The most potent of these inhibitors that have been successfully used are Bad-like BH3 mimetics such as ABT-737 and ABT-263. These antagonist drugs bind with high affinity to Bcl-2 and Bcl-xL in order to upregulate apoptosis.

The Bcl-2 protein family consists of proteins that contain at least one evolutionarily conserved BH domain out of the four that exist (BH1, BH2, BH3, BH4).  Within this family, there exists pro-apoptotic proteins and anti-apoptotic proteins that interact to govern the fate of the cell. Anti-apoptotic proteins conserve all four BH domains, and include Bcl-2, Bcl-XL, Bcl-W, Mcl-1, and A1. Pro-apoptotic proteins can be subdivided into two groups, those with multiple BH domains such as Bax and Bak, and those with only the BH3 domain such as Bid, Bim, Bad, PUMA, and NOXA (Carter, 2016).

When the cell is not undergoing apoptosis, anti-apoptotic proteins such as Bcl-2 and Bcl-XL sequester Bax and Bak.  When the cell wishes to undergo apoptosis, the anti-apoptotic proteins are sequestered by the BH3-only pro-apoptotic proteins, releasing Bax and Bak, which allow the release of cytochrome C from the mitochondrial membrane, uncoupling the electron transport chain and inducing the activity of caspases. In healthy cells, p53 is a transcription factor for the pro-apoptotic BH3-only proteins Bik, Bid, PUMA, NOXA, as well as for Bax, the pro-apoptotic protein with BH1, BH2, and BH3 homology and the most downstream member of the Bcl-2 family in the regulation of apoptosis (Fridman, 2003). In high grade serous ovarian carcinoma, anti-apoptotic proteins including Bcl-2 and Bcl-xL are overactive and therefore responsible for keeping cancerous cells alive too long (Yokohama, 2017). Different studies have shown a negative correlation between Bcl-xL levels and drug sensitivity in regards to chemotherapy.

When the cell is not undergoing apoptosis, anti-apoptotic proteins such as Bcl-2 and Bcl-XL sequester Bax and Bak.  When the cell wishes to undergo apoptosis, the anti-apoptotic proteins are sequestered by the BH3-only pro-apoptotic proteins, releasing Bax and Bak, which allow the release of cytochrome C from the mitochondrial membrane, uncoupling the electron transport chain and inducing the activity of caspases.  In healthy cells, p53 is a transcription factor for the pro-apoptotic BH3-only proteins Bik, Bid, PUMA, NOXA, as well as for Bax, the pro-apoptotic protein with BH1, BH2, and BH3 homology and the most downstream member of the Bcl-2 family in the regulation of apoptosis.  Due to the fact that the majority of TP53 mutations present in HGSOC are in its DNA binding region, the transcriptional activation effect of p53 no longer is present for these pro-apoptotic proteins.  The major problem is that many of the BH3-only pro-apoptotic proteins responsible for inhibition of the anti-apoptotic proteins that, when active, inhibit the pro-apoptotic proteins Bax and Bak, do not get transcribed enough without functional p53.