Replies to post #32727 on Biotech Values

[jazzbeerman]

Dew, exactly, re: metastasis,


Earlier work noticed the many roles macrophages play, and that understanding has grown quite a bit in recent years (as to why).


Here are three recent abstracts for you-
(Out of literally dozens I could point you to. Let me know if you'd like to see more).





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J Leukoc Biol. 2006 Jul 24;

Dual role of macrophages in tumor growth and angiogenesis.



During the neoplastic progression, macrophages as well as dendritic and NK cells are attracted into the tumor site and initiate the immune response against transformed cells. They activate and present tumor antigens to T cells, which are then activated to kill tumor cells. However, tumor cells are often capable of escaping the immune machinery. As the immune surveillance is not sufficient anymore, tumor-associated macrophages contribute to tumor progression. It is notable that tumor-associated macrophages promote the proliferation of tumor cells directly by secreting growth factors. They also participate in tumor progression by acting on endothelial cells and thus promoting the neovascularization of the tumor. Tumor-associated macrophages are indeed key protagonists during angiogenesis and promote each step of the angiogenesis cascade.



I've posted a link to the full paper, which is a must read, at the bottom of this post.






Cancer cell immune escape and tumor progression by exploitation of anti-inflammatory and pro-inflammatory responses.

Apoptotic cells can be eliminated by phagocytosis, which is mediated by antigen-presenting cells (APCs), such as macrophages and dendritic cells (DCs), through phosphatidylserine (PS) on apoptotic cells and phosphatidylserine receptor (PSR) on APCs. The phagocytosis of apoptotic cells by macrophages is strictly regulated by not only the inflammatory reaction, but also by an increase in anti-inflammatory factors such as IL-10, TGF-beta, and prostaglandin E2 (PGE2), leading to an anti-inflammatory situation, whereby apoptosis contributes to a noninflammatory response. However, because PS and PSR are expressed in cancer cells, shed soluble phosphatidylserine (sPS) can interact with the PS receptor on macrophages, which promotes an anti-inflammatory response to macrophages that may lead to immune escape. The sPS derived from cancer cells also reacts with the PSR on the cancer cells to produce IL-10, TGF-beta, and PGE2, which can cause suppression of anti-tumor immunity through the anti-inflammatory response to macrophages, which produces tumor-associated macrophages. Furthermore, sPS and TGF-beta inhibit the maturation of immature DCs, resulting in a functional inhibition of DCs. The potential roles of PS and PSR in cancer cells and macrophages in immune escape mediated by sPS and anti-inflammatory factors are discussed, which may explain their dual regulation of anti- and pro-inflammatory responses during tumor progression.




(I will add that CURRENT work (unpublished, here in America) is proving that exposed phosphatidylserine is responsible for VEGF production from tumor-associated macrophages). It all makes sense that the big initial "apoptotic-looking" signal is what throws the switch for the rest of the downstream pro-angiogenic events....) It also makes one wonder- Why try to gum up VEGF when the real instigator for it's production in the tumor is still sitting there causing the production of more VEGF?....








here's another-





Cancer Res. 2006 Jun 1;66(11):5527-36.

Tumor-driven evolution of immunosuppressive networks during malignant progression.



Tumors evolve mechanisms to escape immune control by a process called immune editing, which provides a selective pressure in the tumor microenvironment that could lead to malignant progression. A variety of tumor-derived factors contribute to the emergence of complex local and regional immunosuppressive networks, including vascular endothelial growth factor, interleukin-10, transforming growth factor-beta, prostaglandin E(2), and soluble phosphatidylserine, soluble Fas, soluble Fas ligand, and soluble MHC class I-related chain A proteins. Although deposited at the primary tumor site, these secreted factors could extend immunosuppressive effects into the local lymph nodes and the spleen, promoting invasion and metastasis. Vascular endothelial growth factors play a key role in recruiting immature myeloid cells from the bone marrow to enrich the microenvironment as tumor-associated immature dendritic cells and tumor-associated macrophages. The understanding of the immunosuppressive networks that evolve is incomplete, but several features are emerging. Accumulation of tumor-associated immature dendritic cells may cause roving dendritic cells and T cells to become suppressed by the activation of indoleamine 2,3-dioxygenase and arginase I by tumor-derived growth factors. Soluble phosphatidylserines support tumor-associated macrophages by stimulating the release of anti-inflammatory mediators that block antitumor immune responses. Soluble Fas, soluble FasL, and soluble MHC class I-related chain A proteins may help tumor cells escape cytolysis by cytotoxic T cells and natural killer cells, possibly by counterattacking immune cells and causing their death. In summary, tumor-derived factors drive the evolution of an immunosuppressive network which ultimately extends immune evasion from the primary tumor site to peripheral sites in patients with cancer.




I will mention that startling antitumor results of blocking PS is not theory. Here are some in vivo examples- (and don't forget Peregrine's single-dose HCV clinical trial results, which are the first human data of PS-blocking)
http://www.investorshub.com/boards/read_msg.asp?message_id=11736683





and finally, here's the full paper of the first abstract I posted above- very relevant which I think you'll find interesting, a good summary of the current understanding of tumor immune evasion. -

http://www.jleukbio.org/cgi/rapidpdf/jlb.1105656v1





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j

[croumagnon]

"cancer stem cells are at the core of every metastasis"

Very interesting article Dew. If the above statement is true, wouldn't that mean that GERN is probably the best long-term cancer play out there? Assuming they can get to a point whereby they can truly target telomers (shorten them at will), then in principle they can stop stem cell metastasis in its track. Certainly this could promote the aging of the whole body as well, but killing the main cancer killer may be the most important target for advanced metastasis cases.

[DewDiligence]

OSIP – Here’s an interesting post by Ricardouno
in reply to the NYT article on metastasis. This
has some relevance for ADH too (#msg-11187383).

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15-Aug-06 08:40 am

Thanks for that summary article....quite interesting.

One of the areas discussed was EMT or epithelial to mesenchymal transition.

This is an area of research of great interest which OSI is pursuing with Tarceva. It is postulated that Tarceva may be significantly more effective before EMT takes place ( that is, generally. earlier in tumor development ). It may serve as a rationale for the use of Tarceva as front-line and especially adjuvant therapy.

From the OSI website comes the following:

http://phx.corporate-ir.net/phoenix.zhtml?c=70584&p=irol-newsArticle&ID=697465&highlight...

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Epithelial Mesenchymal Transition (EMT) May Predict Sensitivity of Solid Tumors of Epidermal Growth Factor Receptor (EGFR) Inhibitors such as Tarceva(TM)

Graeme Griffin et al (abstract #2313) presented pre-clinical data showing that cell lines and tumor xenografts that express epithelial markers (e.g. E-cadherin and (gamma) catenin) may be more sensitive to Tarceva (erlotinib) than cell lines and tumor xenografts that express mesenchymal markers (e.g. vimentin and fibronectin). These biological markers are associated with a process termed Epithelial Mesenchymal Transition (EMT). EMT is thought to be a marker of tumor progression, with tumors that express mesenchymal markers having a greater tendency to be invasive and metastasize than those tumors only expressing epithelial markers. Tumors expressing mesenchymal markers are thought to have a worse prognosis than tumors expressing epithelial markers. This new data supports the hypothesis that Tarceva may be effective in earlier-stage disease, such as an adjuvant or front-line setting in lung cancer, since these earlier-stage tumors are likely to be more epithelial-like in their histology. OSI, together with its alliance partners, Genentech and Roche, anticipate the initiation of clinical trials for Tarceva in both the front-line and adjuvant settings in lung cancer as part of the ongoing Tarceva clinical program.

"The implications of this work are very significant," stated Neil Gibson, Ph.D., OSI's Vice President of Research. "By understanding the role of EMT in solid tumors we believe we will be better positioned to expand the use of Tarceva to disease settings enriched with patients whose tumors are more 'epithelial' in nature thus allowing the evaluation of Tarceva across a broad range of solid tumor types such as colon cancer, breast cancer, head and neck cancer, ovarian cancer and prostate cancer. We look forward to continued pursuit of this emerging area of interest for the oncology community."
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[DewDiligence]

Weizmann Scientists Discover a Control Mechanism for Metastasis

http://www.eurekalert.org/pub_releases/2007-08/wios-wis080807.php

>>
8-Aug-2007

Metastasis – when cancer cells dissociate from the original tumor and migrate via the blood stream to colonize distant organs – is the main cause of cancer death. A team of scientists at the Weizmann Institute of Science has now revealed new details about the mechanisms controlling metastasis of breast cancer cells. Their findings, published recently online in Nature Cell Biology, add significantly to the understanding of metastasis and may aid, in the future, in the development of anti-cancer drugs.

For a cell such as a cancer cell to migrate, it first must detach itself from neighboring cells and the intercellular material to which it is anchored. Before it can do this, it receives an order from outside the cell saying: 'prepare to move.' This signal takes the form of a substance called a growth factor, which, in addition to controlling movement, can activate a number of processes in the cell including division and differentiation. The growth factor attaches to a receptor on the cell wall, initiating a sequence of changes in the cellular structure. The cell’s internal skeleton – an assembly of densely-packed protein fibers – comes apart and the protein fibers then form thin threads on the outside of the cell membrane that push the cell away from its neighbors. In addition, a number of protein levels change: some get produced in higher quantities and some in less.

To understand which proteins are modulated by the growth factor and the nature of the genetic mechanisms involved in cancer cell migration, a team of researchers pooled their knowledge and resources. This team, headed by Prof. Yosef Yarden of the Weizmann Institute’s Biological Regulation Department and his research group, including Drs. Menachem Katz, Ido Amit and Ami Citri; Tal Shay, a student in the group of Prof. Eytan Domany of the Physics of Complex Systems Department; and Prof. Gideon Rechavi of the Chaim Sheba Medial Center at Tel Hashomer.

To begin with, the team mapped all of the genetic changes that take place in the cell after the growth factor signal is received. As they sifted through the enormous amount of data they received, including details on every protein level that went up or down, one family of proteins stood out. Tensins, as they’re are called, are proteins that stabilize the cell structure. But to the scientists' surprise, the amounts of one family member rose dramatically while, at the same time, the levels of another dropped.

Despite the familial similarity, the team found a significant difference between them. The protein that drops off has two arms: One arm attaches to the protein fibers forming the skeleton, and the other anchors itself to the cell membrane. This action is what stabilizes the cell’s structure. The protein that increases, on the other hand, is made up of one short arm that only attaches to the anchor point on the cell membrane. Rather than structural support, this protein acts as a kind of plug, blocking the anchor point, and allowing the skeletal protein fibers to unravel into the threads that push the cells apart. The cell is then free to move, and, if it’s a cancer cell, to metastasize to a new site in the body.

In experiments with genetically engineered cells, the scientists showed that the growth factor directly influences levels of both proteins, and that these, in turn, control the cells’ ability to migrate. Blocking production of the short tensin protein kept cells in their place, while overproduction of this protein plug increased their migration.

Next, the scientists carried out tests on tumor samples taken from around 300 patients with inflammatory breast cancer, a rare but swift and deadly form of the disease, which is associated with elevated growth factor levels. The scientists found a strong correlation between high growth factor activity and levels of the 'plug' protein. High levels of this protein, in turn, were associated with cancer metastasis to the lymph nodes – the first station of migrating cancer cells as they spread to other parts of the body.

In another experiment, the scientists examined the effects of drugs that block the growth factor receptors on the cell walls. In patients who received these drugs, the harmful 'plug' proteins had disappeared from the cancer cells. Prof. Yarden: 'The mechanism we identified is clinically important. It can predict the development of metastasis and possibly how the cancer will respond to treatment.' This discovery may, in the future, aid in the development of drugs to prevent or reduce the production of the unwanted protein, and thus prevent metastasis in breast or other cancers.
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[DewDiligence]

Cleveland-Clinic study challenges accepted notions about “personalized” cancer drugs:

http://www.reuters.com/article/2012/12/13/us-science-cancer-dna-idUSBRE8BC19620121213