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Nathan Goodyear

Differential Effects of Dehydroepiandrosterone and Testosterone in Prostate and Colon C... - 0 views

press.endocrine.org/...en.2012-2249

testosterone prostate colon colon cancer cancer NGF nerve growth factor dhea dehydroepiandrosterone

shared by Nathan Goodyear on 19 Nov 14 - No Cached
  • Several studies indicate that DHEA may enhance cancer-promoting activities in several prostate cancer cell lines acting as agonist or antagonist for the intracellular AR
  • the estrogenic metabolites of DHEA, 5a-androstane-3b, 17b-diol (3b-Adiol) and E2 bind to estrogen receptors but not to AR
  • no specific receptor has been identified for DHEA
  • ...16 more annotations...
  • Different members of neurotrophins are expressed during cancer progression, suggesting their involvement in cell proliferation, anoikis protection, and malignancy
  • Regulation of the apoptotic machinery in prostate and colon cancer cells by testosterone occurs rapidly and is initiated at the plasma membrane level through specific membrane-binding sites not involving the classical cytoplasmic AR
  • testosterone exerts potent regulatory effects on prostate and colon cancer cell apoptosis
  • Testosterone increased cell death in a dose-dependent manner
  • testosterone antagonizes the prosurvival effects of DHEA in neuronal cells, blocking its binding to NGF receptors
  • treatment of cells with DHEA exerted a strong antiapoptotic effect,
  • Androgens hold a central role in prostate and colon cancer biology
  • elevated levels of DHEA or its sulfate ester DHEA-sulfate in young adults are associated to low incidence of androgen-dependent tumors
  • DHEA may play a protective role in young prostate
  • The decline of DHEA with aging may contribute to prostate cancer progression associated with advanced age
  • DHEA is an effective antiapoptotic factor, reversing the serum deprivation-induced apoptosis in prostate cancer cells (DU145 and LNCaP cell lines) as well as in colon cancer cells
  • NGF appears to exert similar antiapoptotic actions in both prostate and color cancer cells
  • exposure of prostate DU145 and colon Caco2 cancer cells to testosterone totally blocked the protective effects of both DHEA and NGF. These findings suggest that testosterone acts as an antagonist of DHEA and NGF
  • These findings support the hypothesis that testosterone may inhibit cancer cell growth by antagonizing the proliferative, antiapoptotic effects of endogenous factors, such as DHEA or NGF, in the case of prostate and colon cancer cells
  • intratumor hormonal microenvironment may play a critical role in tumor progression.
  • The paracrine interactions of androgens with locally produced NGF may define tumor cell fate
  • Nathan Goodyear on 19 Nov 14
     
    Full article of previously posted abstract.  Cancers are unique.  Not all cancers are alike.  Whether they are tissue specific or not, cancers are unique.  This article describes the uniqueness of DHEA and Testosterone cancer, with particular attention to colon.
Nathan Goodyear

The river blindness drug Ivermectin and related macrocyclic lactones inhibit WNT-TCF pa... - 0 views

www.ncbi.nlm.nih.gov/...PMC4287931

ivermectin cancer WTF Selamectin

shared by Nathan Goodyear on 19 Mar 18 - No Cached
  • WNT signaling
  • early colon cancers commonly display loss of function of the tumor suppressor Adenomatous polyposis coli (APC), a key component of the β-CATENIN destruction complex
  • Other cancers also show an active canonical WNT pathway; these include carcinomas of the lung, stomach, cervix, endometrium, and lung as well as melanomas and gliomas
  • ...31 more annotations...
  • In normal embryogenesis and homeostasis, the canonical WNT pathway is activated by secreted WNT ligands produced in highly controlled context-dependent manners and in precise amounts. WNT activity is transduced in the cytoplasm, inactivates the APC destruction complex, and results in the translocation of activate β-CATENIN to the nucleus, where it cooperates with DNA-binding TCF/LEF factors to regulate WNT-TCF targets and the ensuing genomic response
  • beyond the loss of activity of the APC destruction complex, for instance throughAPC mutation, phosphorylation of β-CATENIN at C-terminal sites is required for the full activation of WNT-TCF signaling and the ensuing WNT-TCF responses in cancer.
  • The WNT-TCF response blockade that we describe for low doses of Ivermectin suggests an action independent to the deregulation of chloride channels
  • involve the repression of the levels of C-terminally phosphorylated β-CATENIN forms and of CYCLIN D1, a critical target that is an oncogene and positive cell cycle regulator.
  • the Avermectin single-molecule derivative Selamectin, a drug widely used in veterinarian medicine (Nolan & Lok, 2012), is ten times more potent acting in the nanomolar range
  • Ivermectin also diminished the protein levels of CYCLIN D1, a direct TCF target and oncogene, in both HT29 and H358 tumor cells
  • Activated Caspase3 was used as a marker of apoptosis by immunohistochemistry 48 h after drug treatment. Selamectin and Ivermectin induced up to a sevenfold increase in the number of activated Caspase3+ cells in two primary (CC14 and CC36) and two cell line (DLD1 and Ls174T) colon cancer cell types (Fig​(Fig2C).2C). All changes were significative
  • The strong downregulation of the expression of the intestinal stem cell genesASCL2 andLGR5 (van der Flieret al, 2009; Scheperset al, 2012; Zhuet al, 2012b) by Ivermectin and Selamectin (Fig​(Fig2D)2D) raised the possibility that these drugs could affect WNT-TCF-dependent colon cancer stem cell behavior
  • Pre-established H358 tumors responded to Ivermectin showing a ˜ 50% repression of growth
  • Ivermectin hasin vivo efficacy against human colon cancer xenografts sensitive to TCF inhibition with no discernable side effects
  • Ivermectin (Campbellet al, 1983), an off-patent drug approved for human use, and related macrocyclic lactones, have WNT-TCF pathway response blocking and anti-cancer activities
  • these drugs block WNT-TCF pathway responses, likely acting at the level of β-CATENIN/TCF function, affecting β-CATENIN phosphorylation status.
  • anti-WNT-TCF activities of Ivermectin and Selamectin
  • Ivermectin has a well-known anti-parasitic activity mediated via the deregulation of chloride channels, leading to paralysis and death (Hibbs & Gouaux, 2011; Lynagh & Lynch, 2012). The same mode of action has been suggested to underlie the toxicity of Ivermectin for liquid tumor cells and the potentiation or sensitization effect of Avermectin B1 on classical chemotherapeutics
  • the specificity of the blockade of WNT-TCF responses we document, at low micromolar doses for Ivermectin and low nanomolar doses for Selamectin, indicate that the blockade of WNT-TCF responses and chloride channel deregulation are distinct modes of action
  • What is key then is to find a dose and a context where the use of Ivermectin has beneficial effects in patients, paralleling our results with xenografts in mice.
  • Cell toxicity appears at doses greater (> 10 μM for 12 h or longer or > 5 μM for 48 h or longer for Ivermectin) than those required to block TCF responses and induce apoptosis.
  • Our data point to a repression of WNT-β-CATENIN/TCF transcriptional responses by Ivermectin, Selamectin and related macrocylic lactones.
  • (i) The ability of Avermectin B1 to inhibit the activation of WNT-TCF reporter activity by N-terminal mutant (APC-insensitive) β-CATENIN as detected in our screen
  • (ii) The ability of Avermectin B1, Ivermectin, Doramectin, Moxidectin and Selamectin to parallel the modulation of WNT-TCF targets by dnTCF
  • (iii) The finding that the specific WNT-TCF response blockade by low doses of Ivermectin and Selamectin is reversed by constitutively active TCF
  • (iv) The repression of key C-terminal phospho-isoforms of β-CATENIN resulting in the repression of the TCF target and positive cell cycle regulator CYCLIN D1 by Ivermectin and Selamectin
  • (v) The specific inhibition ofin-vivo-TCF-dependent, but notin-vivo-TCF-independent cancer cells by Ivermectin in xenografts.
  • These results together with the reduction of the expression of the colon cancer stem cell markersASCL2 andLGR5 (e.g., Hirschet al, 2013; Ziskinet al, 2013) raise the possibility of an inhibitory effect of Ivermectin, Selamectin and related macrocyclic lactones on TCF-dependent cancer stem cells.
  • the capacity of cancer cells to form 3D spheroids in culture, as well as the growth of these, is also WNT-TCF-dependent (Kanwaret al, 2010) and they were also affected by Ivermectin treatment
  • If Ivermectin is specific, it should only block TCF-dependent tumor growth. Indeed, the sensitivity and insensitivity of DLD1 and CC14 xenografts to Ivermectin treatment, respectively, together with the desensitization to Ivermectin actionin vivo by constitutively active TCF provide evidence of the specificity of this drug to block an activated WNT-TCF pathway in human cancer.
  • Ivermectin has a good safety profile since onlyin-vivo-dnTCF-sensitive cancer xenografts are responsive to Ivermectin treatment, and we have not detected side effects in Ivermectin-treated mice at the doses used
  • previous work has shown that side effects from systemic treatments with clinically relevant doses in humans are rare (Yang, 2012), that birth defects were not observed after exposure of pregnant mothers (Pacquéet al, 1990) and that this drug does not cross the blood–brain barrier (Kokozet al, 1999). Similarly, only dogs with mutantABCB1 (MDR1) alleles leading to a broken blood–brain barrier show Ivermectin neurotoxicity (Mealeyet al, 2001; Orzechowskiet al, 2012)
  • Indications may include treatment for incurable β-CATENIN/TCF-dependent advanced and metastatic human tumors of the lung, colon, endometrium, and other organs.
  • Ivermectin, Selamectin, or related macrocyclic lactones could also serve as topical agents for WNT-TCF-dependent skin lesions and tumors such as basal cell carcinomas
  • they might also be useful as routine prophylactic agents, for instance against nascent TCF-dependent intestinal tumors in patients with familial polyposis and against nascent sporadic colon tumors in the general aging population
  • Nathan Goodyear on 19 Mar 18
     
    Ivermectin, a common anti-parasitic, found to inhibit WTF-TCF pathway and decrease c-terminal phosophorylaiton of Beta-CATENIN all resulting in increased aptosis and inhibition of cancer growth in colon cancer cell lines and lung cancer cell lines.
Nathan Goodyear

The mineral selenium proves itself as powerful anti-cancer medicine - 0 views

www.naturalnews.com/016446.html

selenium cancer

shared by Nathan Goodyear on 12 May 11 - Cached
  • In a December 1996 article in the Journal of the American Medical Association, Dr. Larry Clark presented evidence that supplemental selenium could reduce cancer death rates by as much as 50%
  • patients receiving selenium had a 67% decrease in cancer of the prostate, a 58 percent decrease in colon or rectal cancer and a 45% decrease in lung cancer
  • An article in the Journal of the American Medical Association (JAMA) by Clark et al. (1996) showed that 200 mcg of supplemental selenium a day reduced overall cancer mortality by 50% in humans compared to a placebo group not receiving supplemental selenium
  • ...10 more annotations...
  • In a recent five-year study of nearly 30,000 rural Chinese people, researchers from the NCI found that daily doses of these three nutrients reduced cancer deaths by 13%.
  • In a study in Cancer Letters (Evangelou et al. 1997), animals with malignant tumors given high doses of vitamins C and E and selenium manifested a significant prolongation of the mean survival time. Complete remission of tumors developed in 16.8% of the animals
  • cities and states with high selenium content in the soil also had significantly lower rates of cancer, especially of the digestive and urinary systems.
  • In one study of hundreds of men, a daily intake of 200 micrograms of selenium cut the incidence of prostate cancer by 60 percent.
  • The statistics for breast cancer are particularly striking. "The higher the selenium, the lower the breast cancer
  • In Yugoslavia, scientists studied 33 patients with breast cancer. These women had selenium levels in their bloodstream only half those of healthy volunteers.
  • The overall reduction in cancer incidence was 37% in the selenium-supplemented group; a 50% reduction in cancer mortality was observed over a 10-year period
  • The following are the site-specific reductions in cancer incidence observed in the study: colon-rectal cancers (58%), lung cancer (46%), and prostate cancer (63%)
  • A selenium deficiency appears to increase the risk of prostate cancer fourfold to fivefold
  • It was determined that, as the male population ages, selenium levels decrease, paralleling an increase in prostate cancer
  • Nathan Goodyear on 12 May 11
     
    exhaustive discussion selenium deficiency and increased cancer risk
Nathan Goodyear

Promising role for Gc-MAF in cancer immunotherapy: from bench to bedside - 0 views

www.ncbi.nlm.nih.gov/...PMC5686300

nagalase Gc-MAF cancer

shared by Nathan Goodyear on 29 Jan 18 - No Cached
  • MAF precursor activity has also been lost or reduced after Gc-globulin treatment in some cancer cell lines
  • This appears to result from the deglycosylated ɑ-N-acetylgalactosaminidase (nagalase) secreted from cancerous cells
  • Nagalase has been detected in many cancer patients, but not in healthy individuals
  • ...31 more annotations...
  • Studies have shown that the production of nagalase has a mutual relationship with Gc-MAF level and immunosuppression
  • It has been demonstrated that serum levels of nagalase are good prognosticators of some types of cancer
  • The nagalase level in serum correlates with tumor burden and it has been shown that Gc-MAF therapy progresses, nagalase activity decreases
  • It has been shown that Gc-MAF can inhibit the angiogenesis induced by pro-inflammatory prostaglandin E1
  • The effect of Gc-MAF on chemotaxis or activation of tumoricidal macrophages is likely the main mechanism against angiogenesis.
  • Administration of Gc-MAF stimulates immune-cell progenitors for extensive mitogenesis, activates macrophages and produces antibodies. “This indicates that Gc-MAF is a powerful adjuvant for immunization.”
  • Cancer cell lines do not develop into tumor genes in mouse models after Gc-MAF-primed immunization (29-31) and the effect of Gc-MAF has been approved for macrophage stimulation for angiogenesis, proliferation, migration and metastatic inhibition on tumors induced by MCF-7 human breast cancer cell line
  • The protocol included: "a high dose of second-generation Gc-MAF (0.5 ml) administered twice a week intramuscularly for a total of 21 injections.”
  • Yamamoto et al. showed that the administration of Gc-MAF to 16 patients with prostate cancer led to improvements in all patients without recurrence
  • Inui et al. reported that a 74-year-old man diagnosed with prostate cancer with multiple bone metastases was in complete remission nine months after initiation of GcMAF therapy simultaneously with hyper T/NK cell, high-dose vitamin C and alpha lipoic acid therapy
  • It has also been approved for non-neoplastic diseases such as autism (41), multiple sclerosis (42, 43), chronic fatigue syndrome (CFS) (40), juvenile osteoporosis (44) and systemic lupus erythematous (45).
  • Gc-MAF has been verified for use in colon, thyroid (38), lung (39), liver, thymus (36), pancreatic (40), bladder and ovarian cancer and tongue squamous carcinoma
  • Prostate, breast, colon, liver, stomach, lung (including mesothelioma), kidney, bladder, uterus, ovarian, head/neck and brain cancers, fibrosarcomas and melanomas are the types of cancer tested thus far
  • weekly administration of 100 ng Gc-MAF to cancer at different stages and types showed curative effects at different follow-up times
  • this treatment has been suggested for non-anemic patients
  • Studies have shown that weekly administration of 100 ng Gc-MAF to cancer patients had curative effects on a variety of cancers
  • Because the half-life of the activated macrophages is approximately one week, it must be administered weekly
  • In vivo weekly intramuscular administration of Gc-MAF (100 ng) for 16-22 weeks was used to treat patients with breast cancer
  • individuals harboring different VDR genotypes had different responses to Gc-MAF and that some genotypes were more responsive than others
  • Administration of Gc-MAF for cancer patients exclusively activates macrophages as an important cell in adaptive immunity
  • Gc-MAF supports humoral immunity by producing, developing and releasing large quantities of antibodies against cancer. Clinical evidence from a human model of breast cancer patients supports this hypothesis
  • There is also evidence that confirms the tumoricidal role of Gc-MAF via Fc-receptor mediation
  • It is likely that the best therapeutic responses will be observed when the nutritional and inflammatory aspects are taken together with stimulation of the immune system
  • it should be noted that no harmful side effects of Gc-MAF treatment have been reported, even when it was successfully administered to autistic children
  • The natural activation mechanism of macrophages by Gc-MAF is so natural and it should not have any side effects on humans or animal models even in cell culture
  • Besides the Gc-MAF efficacy on macrophage activity, it can be a potential anti-angiogenic agent (28) and an inhibitor of the migration of cancerous cells in the absence of macrophages (47).
  • Activating or modifying natural killer cells, dendritic cells, DC, CTL, INF and IL-2 have all been recommended for cancer immunotherapy
  • It has been reported that nagalase cannot deglycosylate Gc-MAF as it has specificity for Gc globulin alone
  • inflammation-derived macrophage activation with the participation of B and T lymphocytes is the main mechanism
  • macrophages highly-activated by the addition of Gc-MAF can show tumoricidal activity
  • Previous clinical investigations have confirmed the efficacy of Gc-MAF. In addition to activating existing macrophages, Gc-MAF is a potent mitogenic factor that can stimulate the myeloid progenitor cells to increase systemic macrophage cell counts by 40-fold in four days
  • Nathan Goodyear on 29 Jan 18
     
    great review on Gc-MAF in cancer.  An increase in nagalase blocks Gc-protein to Gc-MAF activity leaving the host immune system compromised.
Nathan Goodyear

Ivermectin: enigmatic multifaceted 'wonder' drug continues to surprise and exceed expec... - 0 views

www.nature.com/ja201711

Ivermectin cancer

shared by Nathan Goodyear on 19 Mar 18 - No Cached
  • The avermectins are known to possess pronounced antitumor activity
  • Over the past few years, there have been steadily increasing reports that ivermectin may have varying uses as an anti-cancer agent, as it has been shown to exhibit both anti-cancer and anti-cancer stem cell properties
  • In human ovarian cancer and NF2 tumor cell lines, high-dose ivermectin inactivates protein kinase PAK1 and blocks PAK1-dependent growth
  • ...13 more annotations...
  • PAK1 is essential for the growth of more than 70% of all human cancers, including breast, prostate, pancreatic, colon, gastric, lung, cervical and thyroid cancers, as well as hepatoma, glioma, melanoma, multiple myeloma and for neurofibromatosis tumors
  • Ivermectin suppresses breast cancer by activating cytostatic autophagy, disrupting cellular signaling in the process, probably by reducing PAK1 expression
  • Cancer stem cells are a key factor in cancer cells developing resistance to chemotherapies and these results indicate that a combination of chemotherapy agents plus ivermectin could potentially target and kill cancer stem cells, a paramount goal in overcoming cancer
  • Triple-negative breast cancers, which lack estrogen, progesterone and HER2 receptors, account for 10–20% of breast cancers and are associated with poor prognosis
  • Ivermectin addition led to transcriptional modulation of genes associated with epithelial–mesenchymal transition and maintenance of a cancer stem cell phenotype in triple-negative breast cancers cells, resulting in impairment of clonogenic self-renewal in vitro and inhibition of tumor growth and metastasis in vivo
  • Ivermectin-induced cytostatic autophagy also leads to suppression of tumor growth in breast cancer xenografts, causing researchers to believe there is scope for using ivermectin to inhibit breast cancer cell proliferation and that the drug is a potential treatment for breast cancer
  • ivermectin synergizes with the chemotherapy agents cytarabine and daunorubicin to induce cell death in leukemia cells
  • Ivermectin inhibits proliferation and increases apoptosis of various human cancers
  • Activation of WNT-TCF signaling is implicated in multiple diseases, including cancers of the lungs and intestine,
  • A new screening system has found that ivermectin inhibits the expression of WNT-TCF targets
  • It represses the levels of C-terminal β-catenin phosphoforms and of cyclin D1 in an okadaic acid-sensitive manner, indicating its action involves protein phosphatases
  • In vivo, ivermectin selectively inhibits TCF-dependent, but not TCF-independent, xenograft growth without side effects
  • ivermectin has an exemplary safety record, it could swiftly become a useful tool as a WNT-TCF pathway response blocker to treat WNT-TCF-dependent diseases, encompassing multiple cancers.117
  • Nathan Goodyear on 19 Mar 18
     
    Ivermectin shows promise and usefullness in several cancer types.  This is a review article.
Nathan Goodyear

PLOS ONE: Microbial Dysbiosis in Colorectal Cancer (CRC) Patients - 0 views

journals.plos.org/...article

dybsiosis cancer colon cancer Bacteroidetes Prevotella IL-17

shared by Nathan Goodyear on 26 Feb 15 - No Cached
  • differences in the colon microbiota in individuals with colon cancer versus those with a normal colonoscopy
  • qPCR revealed significant elevation of the Bacteroides/Prevotella population in cancer patients that appeared to be linked with elevated IL17 producing cells in the mucosa of individuals with cancer.
  • Bacteroides genus populations and more specifically those of Bacteroides fragilis, have recently been shown to produce a metalloprotease in colon cancer patients, but not in controls [12] suggesting this species sub population might favor carcinogenesis
  • ...3 more annotations...
  • It is noteworthy that among the many mechanisms that may mediate associations between microbiota and human health [21]–[22], pro-inflammatory and immune cell activation in colon mucosa are of great importance in relation to malignancy
  • B. fragilis has been shown to induce mucosal regulatory T-cell responses in the intestine involving TH17 cell recruitment in experimental models
  • the elevations of Bacteroides in the stool and/or IL17 immunoreactive cells in the normal mucosa appear to be promising sensitive markers
  • Nathan Goodyear on 26 Feb 15
     
    A relationship between dysbiosis and colon cancer appears to be present.  Particularly an increase in Bacteroidetes and Prevotella species were found in those with colon cancer versus those without.  An inflammatory up regulation of IL-17 appears to be involved.  Whether this is a cause or effect is yet to be determined, but the presence of elevated Bacteroidetes species with increased IL17 could be used as sensitive biomarkers.
Nathan Goodyear

Tumor regionalization after surgery: Roles of the tumor microenvironment and neutrophil... - 0 views

www.nature.com/...s12276-022-00784-2

TME NETosis metastasis surgery cancer tumor microenvironment

shared by Nathan Goodyear on 20 Apr 23 - No Cached
  • tumor surgery must be carefully considered because the risk of metastasis could be increased by the surgical procedure.
  • NETosis, which is the process of forming neutrophil extracellular traps (NETs)
  • surgery-induced metastasis
  • ...61 more annotations...
  • surgery per se can promote cancer metastasis through a series of local and systemic events
  • surgery results in a serious wound that disrupts the structural barrier preventing the outspreading of cancer cells, change the properties of the cancer cells and stromal cells remaining in the tumor microenvironment, or impairs the host defense systems against cancers
    • Nathan Goodyear
      Nathan Goodyear on 23 Apr 23
       
      Key point; add to presentation on surgery and metastasis
  • After the primary tumor is surgically removed, the metastases can start to grow vigorously via neoangiogenesis because the circulating inhibitors disappear
  • infection and inflammation during the postoperative period have been reported to increase the risk of cancer recurrence in patients
  • Surgeons have long suspected that surgery, even if it is a necessary step in cancer treatment, facilitates cancer metastasis
  • Surgery-induced cancer metastasis has been well established in animal models
  • tumor cell dissemination, tumor-favoring immune responses, and neoangiogenesis
  • the surgical resection of primary tumors is beneficial is controversial
  • CTCs abruptly increase just after surgery
  • Even externally palpitating tumors for diagnosis could increase the numbers of CTCs in skin cancer and breast cancer
  • excessive glucocorticoids negatively modulate immune functions
  • immune surveillance against tumors is considered to be impaired by surgical stress
  • In addition to glucocorticoids, during stimulation of the HPA axis, the catecholamine hormones epinephrine and norepinephrine are released from the adrenal medulla
  • NK cell suppression may be attributed to increased levels of catecholamines as well as glucocorticoids
  • In mice bearing a primary tumor, it was observed that the removal of the primary tumor facilitated the growth of highly vascularized metastases
  • primary tumors may secrete angiogenic inhibitors as well as angiogenic activators
  • second phase of tumor recurrence and metastasis, which are newly acquired events, rather than just outcomes of incomplete treatment.
    • Nathan Goodyear
      Nathan Goodyear on 23 Apr 23
       
      Another key point
  • double-edged sword
  • HIF-1 in neutrophils plays a critical role in NETosis and bacteria-killing activity
  • neutrophils play various roles in the initiation and progression of cancer
  • NETosis
  • many inflammatory and neoplastic diseases
  • formation of neutrophil extracellular traps (NETs), which are large extracellular complexes composed of chromatin and cytoplasmic/granular proteins1
  • NETosis has been highlighted as an inflammatory event that promotes cancer metastasis
  • Once activated, neutrophils produce intracellular precursors by using DNA, histones, and granular and cytoplasmic proteins and then spread the mature form of NETs out around themselves
  • A series of these events is called NETosis.
  • neutrophil elastase, myeloperoxidase, cathepsin G, proteinase 3, lactoferrin, gelatinase, lysozyme C, calprotectin, neutrophil defensins, and cathelicidins
  • innate immune response against infection
  • Neutrophils are the most abundant type of granulocytes, comprising 40–70% of all white blood cells
  • two types of NEToses, suicidal (or lytic) NETosis and vital NETosis
  • Suicidal NETosis mainly depends on the production of reactive oxygen species (ROS)
  • Since neutrophils die during this process, it is called suicidal NETosis.
  • vital NETosis
  • vital NETosis occurs independently of ROS production
  • Vital NETosis can be induced by Gram-negative bacteria. LPS
  • NETs are present in a variety of cancers, such as lung cancer, colon cancer, ovarian cancer, and leukemia
  • neutrophils actively undergo NETosis in the tumor microenvironment
  • Hypoxia
  • NETosis plays a pivotal role in noninfectious autoimmune diseases,
  • cytokines
  • tumor-derived proteases
  • tumor exosomes
  • NETosis generally actively progresses in the tumor microenvironment.
  • the proliferative cytokines TGFβ and IL-10 and the angiogenic factor VEGF are representative of neutrophil-derived tissue repair proteins.
  • NETosis is a defense system to protect the body from invading pathogens
  • when neutrophils are excessively stimulated, they produce excess NETs, thereby leading to pathological consequences
  • plasma levels of NETosis markers are elevated after major surgeries
  • local invasion, intravasation into the blood or lymphatic vessels, escape from the immune system, anchoring to capillaries in target organs, extravasation into the organs, transformation from dormant cells to proliferating cells, colonization to micrometastases, and growth to macrometastases
  • NETs promote metastasis at multiple steps
  • NETs loosen the ECM and capillary wall to promote the intravasation of cancer cells
  • NETs and platelets wrap CTCs, which protects them from attack by immune cells and shearing force by blood flow
  • NETs promote the local invasion of cancer cells by degrading the extracellular matrix (ECM)
  • neutrophil elastase, matrix metalloproteinase 9, and cathepsin G
  • NETs also promote the intravasation of cancer cells
  • millions of tumor cells are released into the circulation every day,
  • NETs can wrap up CTCs with platelets
  • β1-integrin plays an important role in the interaction between CTCs and NETs
  • NET-platelet-CTC aggregates.
  • After metastasizing to distant tissues, tumor cells are often found to remain dormant for a period of time and unexpectedly regrow late
  • NETs are believed to participate in the reactivation of dormant cancer cells in metastatic regions
  • NET-associated proteases NE and MMP-9 were found to be responsible for the reactivation of dormant cancer cells
  • Nathan Goodyear on 20 Apr 23
     
    Surgery induced metastasis: it is real and steered by NETosis.
Nathan Goodyear

Inborn-like errors of metabolism are determinants of breast cancer risk, clinical respo... - 0 views

www.ncbi.nlm.nih.gov/...PMC6114970

cancer metabolism breast cancer glutamine glutamate aspartate oncogenes

shared by Nathan Goodyear on 24 Sep 18 - No Cached
  • We now recognize that human cancers evolve in an environment of metabolic stress. Rapidly proliferating tumor cells deprived of adequate oxygen, nutrients, hormones and growth factors up-regulate pathways that address these deficiencies to overcome hypoxia (HIF), vascular insufficiency (VEGF), growth factor deprivation (EGFR, HER2) and the loss of hormonal support (ER, PR, AR) all to enhance survival and proliferation
  • RAS, PI3K, TP53 and MYC
  • The results suggest that breast cancer could be preceded by systemic subclinical disturbances in glucose-insulin homeostasis characterized by mild, likely asymptomatic, IEM-like biochemical changes
  • ...16 more annotations...
  • The process would include variable periods of hyperinsulinemia with the consequent systemic MYC activation of glycolysis, glutaminolysis, structural lipidogenesis and further exacerbation of hypoglycemia, the result of MYC's known role as an inhibitor of liver gluconeogenesis
  • The metabolic changes we describe in breast cancer arise in concert with IEM-like changes in oxidative phosphorylation as detected by increased values of the ratio lactate/pyruvate (Supplementary Table 2A, 2B) characteristic of Ox/Phos deficiency [25]. In our study, 76% (70/92) of the European breast cancer patients had lactate/pyruvate ratios values higher than the normal value of 25.8
  • four-fold higher frequency of cancer (including breast) in patients with energy metabolism disorders
  • growing recognition that cancer cells differ from their normal counterparts in their use of nutrients, synthesis of biomolecules and generation of energy
  • glutamine concentrations in the cancer patients were reduced to nearly 1/8 of the levels observed in the normal population
  • blood concentrations of aspartate (p = 1.7e-67, FDR = 8.3e-67) (Figure ​(Figure1E)1E) and glutamate (p = 6.4e-96, FDR = 6.2e-95) (Figure ​(Figure1F)1F) were nearly 10 fold higher than the normal ranges of 0–5 μM/L and 40 μM/L, respectively
  • glutamine consumption associated with parallel increases in glutamate and aspartate (Figure ​(Figure1A1A red arrows) is considered a hallmark of MYC-driven “glutaminolysis”
  • Gln/Glu ratio inversely correlates with i- late stage metabolic syndrome and with ii- increased chance of death
  • changes in glutamine consumption, reflected by the Gln/Glu ratio could provide a metabolic link between breast cancer initiation and diabetes, reflective of a systemic metabolic reprogramming from glucose to glutamine as the preferred source of precursors for biosynthetic reactions and cellular energy
  • lower Gln/Glu ratios inversely correlated with insulin resistance and the risk of diabetes
  • the metabolic dependencies of cancer characterized by excessive glycolysis, glutaminolysis and malignant lipidogenesis, previously considered a consequence of local tumor DNA aberration [23] could, instead, represent a systemic biochemical aberration that predates and very likely promotes tumorigenesis
  • these metabolic disturbances would be expected to remain extant after therapeutic interventions
  • accumulation of very long chain acylcarnitines such as C14:1-OH (p = 0.0, FDR = 0.0), C16 (p = 0.0, FDR = 0.0), C18 (p = 0.0, FDR = 0.0) and C18:1 (p = 1.73e-322, FDR = 1.16-321) and lipids containing VLCFA (lysoPC a C28:0) (p = 1.14-e95, FDR = 1.65e-95) in the blood of breast and colon cancer patients
  • Among the most powerful metabolic equations for MYC-activation is that which links the widely used MYC-driven desaturation marker ratio of SFA/MUFA to the MYC glutaminolysis-associated ratio of (Asp/Gln)
  • liver dysfunction shares many features with both IEM and cancer suggesting a role for hepatic dysfunction in carcinogenesis
  • cancer “conscripts” the human genome to meet its needs under conditions of systemic metabolic stress
  • Nathan Goodyear on 24 Sep 18
     
    Breast cancer is a metabolic disease.  Now, where have I heard that cancer is a metabolic disease?
Nathan Goodyear

Cancers | Free Full-Text | A Second WNT for Old Drugs: Drug Repositioning against WNT-D... - 0 views

www.mdpi.com/htm

cancer Niclosamide ivermectin Wnt

shared by Nathan Goodyear on 16 Apr 18 - No Cached
  • To date nearly half of known human tumors show a dysregulation of the WNT signaling pathway
  • It should be also noted that the WNT pathway is not exclusively employed during development or overactivated in cancer. In adults many healthy tissues rely on it for renewal and homeostasis maintenance, most notably the intestine, haematopoietic system, hair, bones and skin. Therefore one might expect adverse reactions in all these organ systems, which has indeed been observed for many WNT-targeting compounds upon attempts to push them into the clinics
  • The intestine seems to be the most vulnerable in this regard
  • ...8 more annotations...
  • Ivermectin inhibits proliferation of human colon cancer and lung cancer cells both in vitro and in vivo
  • The anti-proliferative action, affecting both the bulk tumor cells and CSCs, was linked in this study to inhibition of WNT signaling
  • the anti-WNT IC50 of ivermectin is 5–10 times (~1–2 µM vs. 10 µM) lower than that of its toxic effect against chloride channels
  • oral bioavailability of the drug, as for other antiparasitic drugs discussed in this section, is very low
  • Toxicity studies in vivo have also demonstrated a wide therapeutic index for ivermectin
  • Its anti-proliferative activity has been demonstrated in a wide array of cancer cell lines representative of WNT-dependent cancers: non-small lung carcinoma [96], multiple myeloma [97], hepatoma [98], adrenocortical carcinoma [99], ovarian cancer [100] and glioblastoma
  • Niclosamide inhibits the canonical WNT pathway
  • In addition to inhibiting the canonical WNT pathway, niclosamide may mediate its anticancer activities through several other signaling pathways such as NOTCH [107], MTOR [108], NF-κB [97] and STAT3 [96]
  • Nathan Goodyear on 16 Apr 18
     
    review article highlights older medications that have anti-Wnt pathway effects in cancer.  Roughly, 50% of cancer involve upregulated Wnt pathway activity. Other drugs of note: metformin
Nathan Goodyear

Dietary Insulin Load and Cancer Recurrence and Survival in Patients With Stage III Colo... - 0 views

academic.oup.com/...5038128

insulin diet nutrition cancer colon cancer

shared by Nathan Goodyear on 26 Jun 18 - No Cached
  • Nathan Goodyear on 26 Jun 18
     
    New prospective study of 1023 patients finds that high-insulogenic diet, also know as a traditional American diet, high glycemic, high sugar diet... is associated with an increased risk of cancer recurrence and mortality compared to low insulogenic diet.  The authors concluded that this would be beneficial for after surgical resection in people with stage III colon cancer. My question, is why wait on the development of cancer: use a low-insulogenic diet to prevent the cancer all together or when diagnosed implement immediately.  Why wait? Treat early! Prevent!
Nathan Goodyear

Estrogen Receptors in Colorectal Cancer: Goalkeepers, Strikers, or Bystanders? - 0 views

cancerpreventionresearch.aacrjournals.org/...897.full

estrogen colon cancer ER beta ER-beta breast

shared by Nathan Goodyear on 19 Nov 13 - No Cached
  • one can conclude that ERβ has an overall antiproliferative effect, thereby inhibiting cancer cell proliferation and antagonizing ERα function in the breast
  • HRT with estrogen alone did not increase the risk of breast cancer in the Women's Health Initiative clinical trials program
  • colorectal normal or cancer epithelium does not coexpress ERα and ERβ
  • ...7 more annotations...
  • ERβ expression resulted in the inhibition of proliferation and G1 phase cell-cycle arrest
  • ERβ expression strongly inhibited cMyc and tumor growth in a xenograft mouse model
  • induced ERβ in CRC cells has an antiproliferative, tumor-suppressive function that is independent of ERα
  • ERs also have the ability to bind many other compounds with an estrogen-like structure, including phytoestrogens and xenoestrogens (or endocrine disruptors)
  • Phytoestrogens are a diverse class of natural compounds with structural similarity to estradiol
  • Barone et al. recently found that two ERβ-selective phytoestrogens effectively counteracted CRC tumorigenesis and surprisingly increased ERβ expression in mice with mutations of the tumor-suppressor gene adenomatous polyposis coli
  • We can conclude that estrogens are important in protecting against CRC initiation and progression, and that the protective effect most likely is mediated by ERβ
  • Nathan Goodyear on 19 Nov 13
     
    ER beta is a new potential mode of therapy in colon cancer.  ER beta stimulation has been shown to inhibit colon cancer cell growth.
Nathan Goodyear

Associations between ERα, ERβ, and AR Genotypes and Colon and Rectal Cancer - 0 views

cebp.aacrjournals.org/...2936.full.pdf+html

colon cancer colorectal cancer ER ER alpha ER-alpha ER beta ER-beta HRT estrogen receptors

shared by Nathan Goodyear on 19 Nov 14 - No Cached
  • Nathan Goodyear on 19 Nov 14
     
    Study finds ER-beta plays more significant role in the development of Colon cancer than ER-alpha in women.  HRT in women reduces colon cancer risk in comparison to breast, which is increased.  Shows the different tissue expression of ER-alpha and ER-beta, as well as the HRT itself.
Nathan Goodyear

Tumor Repressive Functions of Estrogen Receptor β in SW480 Colon Cancer Cells - 0 views

cancerres.aacrjournals.org/...6100.long

colon colon cancer cancer estrogen ER beta ER-beta

shared by Nathan Goodyear on 19 Nov 13 - No Cached
  • Nathan Goodyear on 19 Nov 13
     
    Stimulation of ER-beta provides inhibition of colon cancer cell proliferation.  ER-beta is the prominent ER in the colon.
Nathan Goodyear

Diet and Risk of Colorectal Cancer Subtypes Classified by F nucleatum | Colorectal Canc... - 0 views

jamanetwork.com/...2598745

gut microbiota gut flora gut microbiome gut bacteria nutrition diet colon cancer cancer

shared by Nathan Goodyear on 30 Jan 17 - No Cached
  • Nathan Goodyear on 30 Jan 17
     
    Study finds Diet effect colon cancer risk through gut bacteria. Diet higher in fiber and whole grains found to have lower risk of F nucleatum + colon cancer.
Nathan Goodyear

Control of Colon Cancer Development and Progression: Role of Estrogens in Colorectal Ca... - 0 views

www.medscape.com/...576817_3

colon colon cancer cancer estrogen ER beta ER-beta

shared by Nathan Goodyear on 19 Nov 13 - No Cached
  • Nathan Goodyear on 19 Nov 13
     
    Estrogens decrease colon cancer risk likely via ER beta activity.
Nathan Goodyear

Dietary glycemic index, glycemic load, and cancer risk: results from the EPIC-Italy stu... - 0 views

www.nature.com/...s41598-017-09498-2

glucose glycemic index glycemic load cancer diabetes

shared by Nathan Goodyear on 20 Sep 17 - No Cached
  • Nathan Goodyear on 20 Sep 17
     
    High glycemic index diet was found to be associated with increased risk of colon and bladder cancer where as a high glycemic load was associated with increased risk of colon cancer and other diabetes-related cancers.
Nathan Goodyear

Drug Screening Identifies Niclosamide as an Inhibitor of Breast Cancer Stem-Like Cells - 0 views

journals.plos.org/...article

Niclosamide cancer cancer stem cells breast cancer

shared by Nathan Goodyear on 21 Mar 18 - No Cached
  • cancer stem cells may also contribute to tumor formation, metastasis, and treatment resistance
  • Studies have shown that some agents (such as metformin) can selectively target cancer stem cells and that dietary polyphenols, curcumin, peperine, and sulforaphane, which are derived from broccoli/broccoli sprouts, are able to target breast cancer stem cells via inhibition of the Wnt signaling, which affects mammosphere size and colony formation
  • niclosamide inhibits tumor growth and reduces tumor weight
  • ...8 more annotations...
  • Niclosamide treatment inhibited the expression of cyclin D1, Hes1, and PTCH by 33%, 57%, and 79%, respectively
  • The mechanism via which niclosamide, a protonophoric anthelmintic drug, induces stem-like-cell-specific toxicity in breast cancer is interesting. It is an old drug that has been used to treat tapeworms in animals
  • Niclosamide is known to uncouple mitochondrial oxidative phosphorylation during tapeworm killing
  • A screening of autophagy modulators revealed that niclosamide is a novel inhibitor of mTORC1 signaling
  • A recent work also demonstrated that niclosamide induces the apoptosis of myelogenous leukemic cells via the inactivation of NF-kappaB and reactive oxygen species generation
  • Niclosamide was also reported to inhibit Wnt signaling [31]–[33] in colon cancer cells
  • Our recent work demonstrated that niclosamide disrupts multiple metabolic pathways in ovarian-cancer-initiating cells
  • The present study showed that niclosamide treatment resulted in the downregulation of target genes involved in the self-renewal of cancer stem-like cells and inhibited breast SPS
  • Nathan Goodyear on 21 Mar 18
     
    Old ant-parasitic, niclosamide, found to down-regulate cancer stem cell activity.
Nathan Goodyear

Oestrogen and colorectal cancer: mechan... [Int J Colorectal Dis. 2013] - PubMed - NCBI - 0 views

www.ncbi.nlm.nih.gov/...23319136

estrogen estriol estradiol estrone colon cancer ER beta ER-beta

shared by Nathan Goodyear on 19 Nov 13 - No Cached
  • Nathan Goodyear on 19 Nov 13
     
    Estrogen early protects against colon cancer, but estrogen increases proliferation late.  The problem here is the estrogens involved.  If ER beta is shown to be highly expressed in the colon, then Estriol would be of benefit as it preferentially binds to ER beta at a rate of 5:1 and Estradiol at a rate of 1:1.  Estriol is currently used in Europe in advanced breast cancer.
Nathan Goodyear

Molecular Targeting of H/MDM-2 Oncoprotein in Human Colon Cancer Cells and Stem-like Co... - 0 views

pubmed.ncbi.nlm.nih.gov/33419797

colon cancer peptides cancer CSC PNC-27 cancer stem cells PNC27

shared by Nathan Goodyear on 14 Aug 21 - No Cached
  • Nathan Goodyear on 14 Aug 21
     
    PNC-27 selectively kills colon cancer stem cells by binding to membrane H/MDM-2. This was an in vivo study. As with other studies, the result was tumor cell necrosis and associated high LDH release.
Nathan Goodyear

ScienceDirect - Cancer Letters : Antiproliferative potency of structurally distinct die... - 0 views

www.sciencedirect.com/science

Quercetin colon cancer inhibits

shared by Nathan Goodyear on 15 Feb 11 - No Cached
  • Dietary flavonoids are known to be antiproliferative and may play an important role in cancer chemoprevention, especially cancers of the gastrointestinal tract, because of a direct contact with food.
  • Nathan Goodyear on 15 Feb 11
     
    Quercetin shows inhibits growth of colon cancer cells
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