18 replies to this topic

[Cyto]

Gene Hunters Pinpoint New Cancer Gene Target

"We envision future cancer therapy as personalized, based on gene mutations in each patient's tumor," says Velculescu. "This kind of information, gleaned from sequencing a patient's tumor, means drugs could be targeted to just the right molecular pathway at just the right time and potentially be more effective with fewer side effects."

The gene in which the mutations have been found, called PIK3CA, is part of a family of genes encoding lipid kinases, enzymes that modify fatty molecules and direct cells to grow, change shape and move. Although scientists have been studying the biochemical properties of this family of genes for more than a decade, until now, no study revealed that they were mutated in cancer.

In their current experiments, the scientists sequenced the molecular code of the genes in this lipid kinase family and found mistakes in the nucleotides, or DNA building blocks, in one particular gene, called PIK3CA. Each mistake is a result of one nucleotide being switched for another. PIK3CA mutations were found in 32 percent of colon cancer samples (74/234), as well as 27 percent (4/15) of glioblastomas, 25 percent (3/12) of gastric cancers, 8 percent (1/12) breast cancers and 4 percent (1/24) of lung cancers. By studying 76 additional premalignant colon tumors, the scientists found that PIK3CA mutations may occur at or near the time a tumor is about to invade other tissues.

Edited by Mind, 17 February 2012 - 09:46 PM.

[Cyto]

Researchers Find A Protein That Controls Cell Growth

The study sheds light on the relationship between APC and two other proteins involved in the development of cancer -- Skp2 and p27. APC controls the abundance of Skp2, according to the study. Skp2 determines whether a cell will begin the process of making copies of itself, and it was previously tied to p27.

"Only recently has it been realized that Skp2 is a very important oncogene," Dr. Hershko explained in an e-mail. "Dr. Pagano's new study reveals how Skp2 itself is eliminated. This knowledge may be used in the future to down-regulate (decrease the activity of) Skp2 in cancers, and thus to arrest the growth of these cancers."

The gene encoding the p27 protein is one of about twenty so-called "tumors suppressor genes" that have been linked to cancer. When these genes aren't fully activated or are mutated, cells lose their ability to limit their own growth. In previous studies, low levels of the p27 protein have been associated with the development of certain tumors of the breast, colon, lung, esophagus, bone marrow, and thymus. In a sense, APC indirectly controls the abundance of p27.

In more recent studies, researchers have discovered that p27 and Skp2 were inversely correlated in certain tumors, so when Skp2 levels were high, p27 levels were low.

However, no one knew what controlled the cellular abundance of Skp2, which is now considered an oncogene. Alterations in oncogenes often lead to uncontrolled cell growth, and to cancer. Now, with this latest report in Nature, Dr. Pagano's group has figured out that levels of Skp2 are controlled by APC; APC actually induces the degradation of Skp2.

[Cyto]

Cross-Species Comparison Reveals Shared Features Between Tumorigenesis And Organogenesis

"With information derived from the Human Genome Project we now have the ability to easily compare and identify meaningful patterns of gene expression between species such as mouse and human," said Kho, a postdoctoral fellow and the paper's lead author. Such cross-species comparison provides a powerful new tool for understanding the genetic changes associated with human tumor development.

In a developing organ, the pattern of gene expression changes as the individual cells commit to their own specialized functions. By analyzing the changing patterns of expression of more than 2000 genes in the developing cerebellum in mice and comparing these to genes expressed in human medulloblastomas, the investigators were able to characterize the malignant cells from a developmental perspective.

The researchers found that different types of medulloblastomas share many common features with cerebellar cells at the very earliest stages of their development, further emphasizing that malignant cells have disrupted developmental programs. "These findings have exploited our ability to analyze thousands of independently segregating genetic markers to confirm the classic proposals by investigators such as Lobstein and Cohnheim in the 19th century that tumorigenesis recapitulates aspects of development," Rowitch said.

Kohane and Rowitch's research is important for two reasons. Firstly, this novel method provides a generalizable framework within which gene expression in development and tumorigenesis can be studied. By this means, the role of a particular gene in tumor progression can be better understood. And secondly, since this analysis is readily applicable to other tumor types it can be developed as a useful tool for both tumor diagnosis and prognosis.

Being able see how organs grow at the comprehensive genetic level is certainly a killer feat.

[Cyto]

Discovery sheds light on how cancer cells grow and divide

The newly described relationship between Dynamin-2 and the centrosome poses the intriguing possibility that their partnership connects the cell’s surface and its interior via signals that coordinate and organize cell division. This is compelling because cancer, in essence, is cell division out of control. Taking control of a cell’s "switchboard" -- if that’s what this partnership turns out to be -- would be a promising potential strategy to pursue in designing new drugs for cancer treatment.

Just incase, the centrosome is the microtubule-like mechanism which develops the long microtubule arms that are used to pull chromosomes apart during division.

[Cyto]

One step further toward treatment for degenerative diseases

Scientists at McGill University's Faculty of Medicine have discovered a key step that will provide new targets for treatments of many degenerative diseases such as Alzheimer's, Cystic Fibrosis and Diabetes. Dr. David Thomas, Chair of Biochemistry, Dr. John Bergeron, Chair of Anatomy and Cell Biology and colleagues have identified a mechanism by which misfolded proteins are recognized in the cell. This is a critical process as proteins that are not correctly folded or shaped are extremely harmful to cells and are the basis for a number of human degenerative diseases. The findings were published in the prestigious journal Nature Structural and Molecular Biology.
"We have identified a central enzyme that is sensitive to very subtle changes in the folded state of a protein," explained Dr. David Thomas. "Proteins are the building blocks and machines of our bodies. In order for them to work correctly they have to fit together. Cells in our bodies have developed quality control mechanisms to assure proper folding. When something goes wrong, cells can accumulate misfolded proteins that don't work properly. The misfolding of proteins is the basis for a number of neurodegenerative diseases such as Alzheimer's and Parkinson's. Our findings are an important step toward the development of innovative prevention and treatment strategies for such diseases."

Dr. Thomas and Dr. Bergeron, together with graduate student Sean Taylor and post-doctoral fellow Andrew Ferguson, showed that the enzyme UDP-glucose:glycoprotein glucosyltransferase (UGGT) can sense specific regions of disorder and activity of proteins – key steps to recognizing misfolded proteins and removing them from the cells.

[Cyto]

New insight into how tumors resist radiation

Scientists have uncovered new evidence about a critical cellular pathway that makes tumor blood vessels resistant to radiation therapy. The research, published in the May issue of Cancer Cell, may have significant clinical applications, as a better understanding of this mechanism may open new avenues for enhancing the effectiveness of radiation therapy.
Tumor growth and survival is completely dependant upon having an adequate blood supply. In fact, the sensitivity of a tumor's blood vessels to radiation therapy is a major determinant of how successful the treatment will be. Recent studies have shown, however, that tumors can respond to radiation by secreting factors that promote the survival of blood vessel cells. Dr. Mark W. Dewhirst and colleagues from Duke University Medical Center have investigated the activation of this protective response and whether the process can be successfully inhibited, thereby maximizing the effectiveness of radiation therapy. The investigators focused on a molecule called hypoxia inducible factor-1 (HIF-1) that is known to stimulate the production of factors called cytokines that are related to tumor metabolism, growth, and blood vessel formation.

They found that HIF-1 levels were increased in tumors after radiation treatment, and that HIF-1-regulated cytokines decreased the sensitivity of blood vessels to radiation. Based on this knowledge, the investigators demonstrated that administration of low doses of a HIF-1 inhibitor in tumor-bearing mice dramatically enhanced the effectiveness of radiation therapy by destroying tumor blood vessels without having an impact on normal vessels.

These results indicate that HIF-1 acts as a major factor directing resistance of tumor vasculature to radiation therapy. According to Dr. Dewhirst, "We believe that by understanding how this protective response is activated, we can discover an effective means of inhibiting it.

This work takes a major step toward achieving this understanding and might eventually translate into a significant clinical benefit by allowing optimal sensitization of tumor vasculature to conventional therapies including radiation."

[Cyto]

Inhibition of cathepsin proteases inhibits tumor formation in transgenic mice

A new research study provides evidence that inhibition of cathepsin cysteine proteases may be a viable strategy for treatment of human cancers. Cathepsins are shown to be involved in multiple stages of tumor development in transgenic mouse models of cancer, and pharmacological inhibition of cathepsins impairs tumor growth and progression. The research is published in the May issue of Cancer Cell.

Molecules known as proteases have long been linked with cancer in humans, and the cathepsins are known to be associated with some human malignancies. However, a specific role for cysteine cathepsin proteases in tumor progression has not been examined in detail, and cathepsins as a potential therapeutic target for treatment of cancer have not been previously reported. Dr. Matthew Bogyo from Stanford Medical School and Dr. Douglas Hanahan from the University of California at San Francisco and colleagues demonstrated that cathepsins are elevated in tumors that form in a mouse model of a rare form of pancreatic cancer and a mouse model of cervical cancer. Using specialized chemical reporters that detected enzymatic activity of cathepsins, the researchers revealed that elevated cathepsins activity in tumors was correlated with the formation of tumor blood vessels (angiogenesis), tumor growth, and invasion into normal tissue in these tumor-bearing mice.

Furthermore, treatment of the cancer-prone mice with a pharmacological inhibitor of cysteine cathepsin activity disrupted both early and late stages of tumor development. The effective dose of the inhibitor was not toxic to normal cells, suggesting that it may be a potential candidate for use in the treatment of human cancers.

These results point to cathepsins as a viable target for future anticancer therapeutics. According to Dr. Hanahan, "It is reasonable to suggest that cathepsin inhibitors may show combinatorial benefits with other targeted (and traditional) therapies, which could be revealed in preclinical trials involving this and other mouse models of human cancer."

[Lazarus Long]

Here is an outgrowth of the research demonstrating that aspirin DOES have a broad inhibitory effect on against the formation of malignancy. This article is old but it attempts to explain the mechanism by which this occurs and now a new generation of COX-2 Inhibitors as both preventative and alternative lower impact chemotherapy are being developed.


Image: Courtesy of Hibiki Kawamata, Smith College

http://www.the-scien...s_p_020930.html

Volume 16 | Issue 19 | | Sep. 30, 2002

COX-2 Inhibitors Tackle Cancer Research targets the earliest stages of cancer, aims at chemoprevention
By Ricki Lewis

A drug developer's dream, rationally designed to quell inflammation, COX-2 inhibitors are also prime candidates for preventing cancer or its recurrence. Gary J. Kelloff, chief of the chemoprevention branch at the National Cancer Institute (NCI), lists the requirements for a molecular target such as the COX-2 enzyme: It must be highly expressed in precancer or cancer cells and not in others; blocking it isn't toxic and doesn't disrupt normal function; effects must be measurable; and there must be clinical benefit. "COX-2 is an ideal target," he says.

The COX-2 inhibitors shot to pharmaceutical fame in December 1998, when the Food and Drug Administration approved Celebrex (celecoxib) to treat osteoarthritis and rheumatoid arthritis. Five months later Vioxx (rofecoxib) followed, approved for osteoarthritis, acute pain, and dysmenorrhea.1 But the use for cancer--begun with the 1999 approval of Celebrex to treat a type of colon cancer, familial adenomatous polyposis (FAP)--fits right into NCI's goal to target the earlier stages of cancer, an approach called chemoprevention.2

Specifically, the plan is to target intraepithelial neoplasia, the prelude to invasive cancer, or even earlier stages. "IEN is a precursor lesion that serves as a surrogate endpoint, which is the prevention or decrease in size of this lesion," explains Kelloff. And with an aging population, better diagnostics, and the promise of proteomics, it makes sense to intervene sooner in addition to the traditional later in cancer treatment.

A TALE OF TWO COX ENZYMES COX-2 inhibitors are a refinement of non-steroidal anti-inflammatory drugs (NSAIDs). "The aspirin-like NSAIDs act pharmacologically as an analgesic, anti-inflammatory agent, and they decrease fever. But side effects are gastrointestinal ulceration and bleeding. In the United States each year, 7,000 die from aspirin poisoning," says Makoto Mark Taketo, a professor of pharmacology at Japan's Kyoto University Graduate School of Medicine. It turned out that NSAIDs dampen two forms of the same enzyme, only one of which--COX-1--causes the adverse effects.

NSAIDs inhibit cyclooxygenase (COX), which is synthesized from arachidonic acid in cell membranes. The constitutive or "housekeeping" variant, COX-1, is expressed in many cells all the time, providing basic functions of life. In contrast, the inducible COX-2 is not made in normal epithelium, but causes inflammation and promotes tumor formation in response to growth factors, cytokines, or oncogene signals. COX-2 does so by stimulating production of prostaglandin PGE2, which in turn activates a specific epithelium receptor that in turn increases cyclic AMP production. This stimulates synthesis of vascular endothelial growth factor (VEGF), which triggers the angiogenesis that helps a tumor spread. Taketo and his group worked out the steps to this pathway by knocking out the various players in mice, looking at cells of colon polyps that model FAP in humans.

Because NSAIDs inhibit both COX enzymes, yet COX-2 does not cause the adverse effects and is produced early in carcinogenesis, it made sense to develop a drug to block only it. "Drugs that inhibit COX-2 are small enough to hit a pocket that exists in COX-2 but not in COX-1. This is the basis of the specificity," says Taketo.

Evidence that COX-2 inhibitors intervene early in the development of cancer emerged epidemiologically. Clinicians noticed that people who regularly take NSAIDs--usually to combat the inflammation of arthritis or to prevent heart attacks--have very low incidence of colorectal cancer. An early case report of disappearing FAP polyps in a patient taking a nonspecific NSAID, sulindac,3 inspired placebo- controlled clinical trials to assess the ability of low or high doses of sulindac4 or Celebrex5 to slow progression of FAP. The evidence is overwhelming, and mounting. "A 15- to 20-year block of data shows that NSAIDs block cancer--42 of 43 colon cancer studies show this effect," says Kelloff.

Because COX-2 expression peaks at a particular stage of pathogenesis, timing of cancer treatment to block the enzyme may be crucial. The 1993 study from professor of medicine Francis M. Giardiello and colleagues at Johns Hopkins noted that COX-2 inhibition lost effectiveness after six months of treatment.4 Perhaps in this time, cancer cells that are resistant to COX-2 inhibition persist and accumulate as sensitive cells are wiped out, leading to drug resistance. The group's latest report follows 41 patients with FAP for four years, and reveals that nine of 21 (43%) individuals given sulindac had recurrent polyps, compared to 11 of 20 (55%) people given placebo.6 The researchers did not consider these distinctions to be significant, suggesting that efficacy of COX-2 inhibition drops off with time.

BEYOND THE COLON Oncologists hope that the COX-2 inhibitors that work so well on FAP will also help individuals who have more common forms of colon cancer. The drugs also work against FAP polyps growing in areas other than the colon. Kelloff's group assessed the effects of six months of Celebrex at low or high dose vs. placebo on the duodenum in FAP patients, monitoring the change (in percent) of the small intestine lining covered in polyps.7 The polyp area decreased much more (14.5%) in the patients given high doses compared to the placebo group (1.4%). In the most severely affected patients, Celebrex reduced the affected area 31%.

COX-2 inhibitors may also be effective on cancers that originate in the small intestine. Researchers from Hirosaki University School of Medicine in Japan found COX-2 production in all 26 patients they examined with Helicobacter pylori-associated intestinal-type gastric cancer, but not in four patients with diffuse gastric cancer. In addition, they found that COX-2 is predominant in the precancerous metaplasia stage, and suggest that the drugs be investigated further as an early treatment.8

Celebrex prevents ultraviolet-induced skin cancer in mice,9 and investigation of this use in humans is well under way.10 A multicenter trial headed by Craig Elmets, a professor of dermatology at the University of Alabama at Birmingham, is following 240 people for nine months who have red, scaly skin lesions called actinic keratoses, which progress to squamous cell carcinoma in 10% of cases. The study will assess whether the drug can prevent new lesions from forming or shrink existing ones. And at the University of California, San Francisco, professor of dermatology Ervin Epstein is leading a study of Celebrex's dampening effects on basal cell nevus syndrome, which can progress to basal cell carcinoma.

A preliminary study of Celebrex to treat non-small-cell lung cancer returns to the biochemical roots of the drug's action. David Johnson, deputy director of the Vanderbilt-Ingram Cancer Center in Nashville, is measuring levels of VEGF and PGE2 in the serum of patients, rather than COX-2 levels in tumor specimens. "In this group of patients, docetaxel [Taxotere] alone produces a median survival of about seven months. We're interested in looking at the combination [of docetaxel and Celebrex] in larger trials if we see a better survival. We're also interested in determining if changes in blood VEGF levels or urinary PGE-M, the metabolite of PGE2, correlate with what we see clinically. If either or both of these parameters correlate with the clinical findings, they could be used as possible surrogates of COX-2 inhibition activity," Johnson explains.

With the exception of the test case of FAP, so far the studies pitting COX-2 inhibitors against various cancers are preliminary, small, and short-term. But researchers anticipate an avalanche of supportive data that will reveal when, for how long, and with what other treatments the drugs should be taken. Taketo concludes: "COX-2 inhibition won't necessarily kill the cancer, but with chemotherapy, it may help to lower the dosage needed, with more effective results."

Ricki Lewis (rickilewis@nasw.org) is a contributing editor.

References
1. R. Lewis, "COX fighting," The Scientist, 14[11]:1, May 29, 2000.

2. J.A. O'Shaughnessy et al., "Treatment and prevention of intraepithelial neoplasia: an important target for accelerated new agent development," Clinical Cancer Research, 8:314-46, 2002.

3. W.R. Waddell, R.W. Loughry, "Sulindac for polyposis of the colon," Journal of Surgical Oncology, 24:83-7, 1983.

4. F.M. Giardiello et al., "Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis," New England Journal of Medicine (NEJM), 328:1313-16, 1993.

5. G. Steinbach et al. "The effect of celecoxib, a cyclooxygenase 2 inhibitor, in familial adenomatous polyposis," NEJM, 342:946-52, 2000.

6. F.M. Giardiello et al., "Primary chemoprevention of familial adenomatous polyposis with sulindac," NEJM, 346:1054-9, April 4, 2002.

7. R.K. Phillips et al., "A randomized, double blind, placebo controlled study of celecoxib, a selective COX 2 inhibitor, on duodenal polyposis in familial adenomatous polyposis," Gut, 50:857-860, June 2002.

8. R. Yamagata et al., "Cyclooxygnease-2 expression is increased in early intestinal-type gastric cancer and gastric mucosa with intestinal metaplasia," European Journal of Gastroenterology and Hepatology, 14:359-63, April 2002.

9. I.F. Orengo et al., "Celecoxib, a cyclooxygenase inhibitor as a potential chemopreventive to UV-induced skin cancer," Archives of Dermatology, 138:751-5, June 2002.

10. A.P. Pentland, "Cyclooxygenase inhibitors for skin cancer prevention," Archives of Dermatology, 138:823-7, June 2002

And here is a separate discussion on the same issue. It is a low cost preventative that could enter in to the regimen of poorer people right now as this drug is globally inexpensive and available, while the improved version and methods are developed.

The Role of COX-2 Inhibitors in Cancer Treatment

[Lazarus Long]

Now this interesting article ties this action of the COX inhibition to the separately understood benefits of Fish Oils and suggests and enzymatic relationship between the actions of these commonly recognized inhibitors. I realize that we have all seen this mentioned before but I thought it interesting to make this update as what has been noticed "anecdotally" is now not only corroborated by independently conducted studies but is being unraveled better for understanding why.

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http://www.ajcn.org/...t/full/79/6/935

American Journal of Clinical Nutrition, Vol. 79, No. 6, 935-945, June 2004
© 2004 American Society for Clinical Nutrition

REVIEW ARTICLE

Dietary long-chain n–3 fatty acids for the prevention of cancer: a review of potential mechanisms 1,2,3
Susanna C Larsson, Maria Kumlin, Magnus Ingelman-Sundberg and Alicja Wolk

1 From the Divisions of Nutritional Epidemiology (SCL and AW), Experimental Asthma and Allergy Research (MK), and Molecular Toxicology (MI-S), The National Institute of Environmental Medicine, Karolinska Institutet, Stockholm.
2 Supported by grants from the Swedish Cancer Society (to AW).
3 Reprints not available. Address correspondence to SC Larsson, Division of Nutritional Epidemiology, The National Institute of Environmental Medicine, Karolinska Institutet, Box 210, SE-171 77 Stockholm, Sweden. E-mail: susanna.larsson@imm.ki.se.


FIGURE 1. Overview of the metabolism of n–6 and n–3 polyunsaturated fatty acids (PUFAs) into eicosanoids involved in inflammation and carcinogenesis. The names of these eicosanoids are shown in bold. LA, linoleic acid (18:2n–6); -LNA, -linolenic acid (18:3n–3); GLA, -linolenic acid (18:3n–6); DGLA, dihomo--linolenic acid (20:3n–6); AA, arachidonic acid (20:4n–6); EPA, eicosapentaenoic acid (20:5n–3); DHA, docosahexaenoic acid (22:6n–3); PLA2, phospholipase A2; LOX, lipoxygenase; COXs, cyclooxygenases (COX-1 and COX-2); 15-HETE, 15(S)-hydroxyeicosatetraenoic acid; 12-HETE, 12-hydroxyeicosatetraenoic acid; 5-HETE, 5-hydroxyeicosatetraenoic acid; HEPE, hydroxyeicosapentaenoic acid; HPETE, hydroperoxyeicosatetraenoic acid; HPEPE, hydroperoxyeicosapentaenoic acid; LT, leukotriene; HODE, hydroxyoctadecadienoic acid; PG, prostaglandin; TX, thromboxane. Link to larger image
(excerpt)

MECHANISMS OF POTENTIAL CHEMOPREVENTIVE EFFECTS OF n–3 FATTY ACIDS ON CARCINOGENESIS 

Mounting evidence shows that dietary n–3 PUFAs inhibit the promotion and progression stages of carcinogenesis. Several molecular mechanisms whereby n–3 PUFAs potentially affect carcinogenesis have been proposed. These mechanisms include 1) suppression of arachidonic acid (AA, 20:4n–6)-derived eicosanoid biosynthesis, which results in altered immune response to cancer cells and modulation of inflammation, cell proliferation, apoptosis, metastasis, and angiogenesis; 2) influences on transcription factor activity, gene expression, and signal transduction, which leads to changes in metabolism, cell growth, and differentiation; 3) alteration of estrogen metabolism, which leads to reduced estrogen-stimulated cell growth; 4) increased or decreased production of free radicals and reactive oxygen species; and 5) mechanisms involving insulin sensitivity and membrane fluidity.

Inhibition of arachidonic acid-derived eicosanoid biosynthesis

One of the more important functions of PUFAs (n–3 and n–6 fatty acids) is related to their enzymatic conversion into eicosanoids (Figure 1), which are short-lived, hormone-like lipids with chain lengths of 20 carbon atoms (eicosa = 20). Eicosanoids are biologically potent and have a wide array of activities: they modulate inflammatory and immune responses and play a critical role in platelet aggregation, cellular growth, and cell differentiation. The precursor fatty acids for the formation of eicosanoids are dihomo--linolenic acid (DGLA, 20:3n–6), AA, and EPA. Linoleic acid (LA, 18:2n–6) and -linolenic acid (-LNA, 18:3n–3) are the predominant plant-derived dietary PUFAs and are the precursors of DGLA and AA and of EPA, respectively. The production of eicosanoids begins with the liberation of PUFAs from membrane phospholipids by the action of various phospholipases.

Thereafter, these PUFAs serve as substrates for cyclooxygenases (COX-1, which is a constitutive enzyme, and COX-2, which is an inducible enzyme), lipoxygenases (5-, 12-, and 15-lipoxygenase), or cytochrome P450 monooxygenases.

The cyclooxygenases give rise to prostaglandins and thromboxanes, whereas the lipoxygenases produce leukotrienes, hydroxy fatty acids, and lipoxins. Cytochrome P450 monooxygenase-mediated oxidation of PUFAs generates hydroxyfatty acids, dihydroxyfatty acids, and epoxy fatty acids. The relative proportions of PUFAs in cell membranes, as well as cell type, are the primary factors in regulating which eicosanoid will be generated. Hydrolytic release of PUFAs from phospholipids appears to occur indiscriminately with n–3 and n–6 PUFAs. Because the major PUFA in cell membranes is AA, most eicosanoids produced will be of the 2-series prostanoids (prostaglandins and thromboxanes) and the 4-series leukotrienes, with 2 and 4 double bonds, respectively, in the products. EPA is a substrate for 3-series prostanoids and 5-series leukotrienes.

In general, AA-derived eicosanoids have proinflammatory effects (39–41)—although prostaglandin E2 (PGE2) has been suggested to also have antiinflammatory properties (42)—whereas EPA-derived eicosanoids have antiinflammatory effects. Eicosanoids generated from AA, such as PGE2, leukotriene B4, thromboxane A2, and 12-hydroxyeicosatetraenoic acid, have been positively linked to carcinogenesis (34). For example, PGE2 promotes tumor cell survival and is found at higher concentrations in cancer cells than in normal cells (43). The mechanisms whereby PGE2 promotes tumor survival include inhibition of apoptosis and stimulation of cell proliferation (44–46). It has also been reported that PGE2 increases tumor progression by promoting tumor angiogenesis (47–49). 12-Hydroxyeicosatetraenoic acid has been shown to suppress apoptosis (50, 51) and promote tumor angiogenesis (52) and tumor cell adhesion to endothelial cells (53, 54); the latter is an essential and early event in the initiation of the metastatic cascade.

Some lipoxygenase products generated from AA, such as leukotriene B4 and 5-hydroxyeicosatetraenoic acid, also play a role in tumor cell adhesion (55) and thus may augment metastatic potential. Leukotriene B4 further enhances generation of reactive oxygen species (40), which may attack DNA and lead to cancer initiation. AA-derived eicosanoids synthesized by the action of cytochrome P450 monooxygenase were recently shown to influence several biological processes, including cell proliferation, apoptosis, and inflammation (56). For example, 14,15-epoxyeicosatrienoic acid inhibits apoptosis (57) and increases cell proliferation (58).

Although several AA-derived eicosanoids have been suggested to promote carcinogenesis, some of them, such as PGI2 (59), 15d-PGJ2 (metabolite of PGD2) (60), and 15(S)-hydroxyeicosatetraenoic acid (61), as well as the LA-derived 13(S)-hydroxyoctadecadienoic acid (62, 63), have been found to suppress cell proliferation and induce apoptosis.

[Mind]

A link between TCPTP and cancer growth

The discovery, published August 11 in the international journal Cancer Cell, provides valuable insights into how cancer cells develop and mutate, and could ultimately change treatment options for sufferers around the world.

Team leader, Associate Professor Tony Tiganis, from the Department of Biochemistry and Molecular Biology at Monash University said their work showed that the enzymes known as protein tyrosine kinases (PTKs) had a greater role than previously thought in the rate of growth and tumour change over time.

"We already know that PTKs are associated with several types of aggressive cancers, including colon, breast and lung cancers," Associate Prof Tiganis said.

"What we have discovered is that PTKs have an important role to play as cancer cells grow and mutate to become potentially more aggressive tumours.

"We have identified one mechanism by which PTKs may remain activated and allow cancer cells to bypass the molecular warden of DNA replication. They may lack a key enzyme called TCPTP." Experiments published in the prestigious journal Cancer Cell have been conducted using cells grown in the laboratory. "But the big question remains. What happens in the real world of human cancers?"

The Monash team will now apply their laboratory findings to human cancer samples to see if they contain low levels of TCPTP and hopefully cement the role of this protein in cancer formation and development.

[Mind]

Amplifying Cell Death Signals May Help With Cancer Treatment

IAP stands for "inhibitor of apoptosis protein," and these proteins do exactly what their name implies. By inhibiting apoptosis, or programmed cell death, they keep cells alive by directly binding to executioner enzymes called caspases. But until now, precisely how IAPs save cells from death has remained unclear.

With graduate student Andrew Schile and postdoc Maria Garcia-Fernandez, Steller studied the X-linked inhibitor of apoptosis protein, or XIAP, and the role of its largely ignored RING domain, which has been implicated in promoting cell death as well as survival. Steller, Schile and Garcia-Fernandez found that genetically targeting and removing RING affected only some cell types in healthy mice. And even though the mice without the RING had more cell death than the mice with the RING, both lived normal lives under normal laboratory conditions.

But when the scientists compared mice that were genetically predisposed to developing cancer, they found that those without the RING lived twice as long as those with it.

"Cancer cells thrive by disabling the molecular machinery that tells sick cells to die," says Steller. "By removing the RING, we wanted to see whether we would trick the machinery to turn back on. And that's what happened. Cells die more readily, making it much more difficult for cancer to be established."

Any new target for cancer is usually good to explore - if it has shown success in other animals - however, I see this one as being more complicated as it changes the process of apoptosis. Just as chemotherapy kills cancer cells and nearly kills the entire organism along with it, I would be worried that changing the apoptosis pathway would carry significant side effects (but I am no expert, so take that with a grain of salt). Seems like an area (apoptosis pathway) that needs a lot more discovery and solid theory before it would be safe as a cancer treatment.

[Mind]

Radiation treatments transform "regular" cancer cells into cancer stem cells.

Researchers with the

UCLA Department of Radiation Oncology

report that radiation treatment — despite killing half of all tumor cells during every treatment —

transforms other cancer cells into treatment-resistant breast cancer stem cells

.

The generation of these breast cancer stem cells counteracts the otherwise highly efficient radiation treatment. If scientists can uncover the mechanisms and prevent this transformation from occurring, radiation treatment for breast cancer could become even more effective, said study senior author Dr. Frank Pajonk, an associate professor of radiation oncology and Jonsson Cancer Center researcher.

“We found that these induced breast cancer stem cells (iBCSC) were generated by radiation-induced activation of the same cellular pathways used to reprogram normal cells into induced pluripotent stem cells (iPS) in regenerative medicine,” said Pajonk, who also is a scientist with the Eli and Edythe Broad Center of Regenerative Medicine at UCLA.

“It was remarkable that these breast cancers used the same reprogramming pathways to fight back against the radiation treatment.”

“Controlling the radiation resistance of breast cancer stem cells and the generation of new iBCSC during radiation treatment may ultimately improve curability and may allow for de-escalation of the total radiation doses currently given to breast cancer patients, thereby reducing acute and long-term adverse effects,” the study states.

I understand their reasoning here and it is good that they are thinking of ways to limit the amount of radiation, but this seems like a BAD result to me. The radiation causes more mutation and the cancer becomes harder to eradicate. I think better targeted, more effective radiation would be the way to go, rather than adding another complicated layer to the treatment.

Edited by Mind, 15 February 2012 - 10:05 PM.

[ihatesnow]

http://www.cancer.uc...URL=/index.aspx

http://www.scienceda...20213185115.htm

Edited by ihatesnow, 17 February 2012 - 12:22 AM.

[ihatesnow]

http://www.pubstemcell.com/

Edited by ihatesnow, 17 February 2012 - 12:40 AM.

[Mind]

P21 might be a target for future cancer therapies. P21 can kill cancer cells even in the absence of P53.

The research also showed that p21 can kill cells even in the absence of p53, a protein that is mostly responsible for cell death but is inactivated in most cancers.

“This shows that certain types of cancer, sarcomas for instance, but maybe also others, should respond well to drugs that increase the levels of p21, even if they don’t have an active p53,” said Macip. “The side effects of these therapies should be minimal, since our experiments show that normal cells would arrest but not die in response to p21.

“There are already drugs available that selectively increase p21. Our results provide a rationale for testing them in certain types of cancers, which could be identified using the experiments we describe.”

[Mind]

Knowing that cancer cells prefer glucose for energy, many Longecity forum participants have suggested a ketogenic or very lo-carb diet (in addition to other treatments)in order to battle cancer. Here is some more evidence that it is probably a beneficial tactic: http://www.scienceda...20626131854.htm

"Most strikingly, our discovery that glucose withdrawal causes both cell death and increased tyrosine phosphorylation is intriguing because increased tyrosine kinase signaling is normally associated with cell growth

," said Nicholas A. Graham, a senior postdoctoral scholar in Graeber's lab who helped design the project.

To explain the seemingly contradictory result that glucose deprivation reduced viability and at the same time increased signaling, the authors used an unbiased systems-biology approach that included phospho-tyrosine mass spectrometry and other biochemical profiling techniques.

Assessing the "crosstalk" between metabolism and signaling, they discovered that the glucose deprivation activates a positive feedback loop whereby the withdrawal of glucose induces increased levels of reactive oxygen species, which in turn inhibit negative regulators of tyrosine signaling. The resulting supra-physiological levels of tyrosine phosphorylation then generate additional reactive oxygen species.

"Because cancer cells live on the edge of what is metabolically feasible, this amplifying cycle of oxidative stress ultimately overwhelms and kills the cancer cell,

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