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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