The autophagic tumor stroma model of cancer or “battery-operated tumor growth”

The role of autophagy in tumorigenesis is controversial. Both autophagy inhibitors (chloroquine) and autophagy promoters (rapamycin) block tumorigenesis by unknown mechanism(s). This is called the “Autophagy Paradox”. We have recently reported a simple solution to this paradox. We demonstrated that epithelial cancer cells use oxidative stress to induce autophagy in the tumor microenvironment. As a consequence, the autophagic tumor stroma generates recycled nutrients that can then be used as chemical building blocks by anabolic epithelial cancer cells. This model results in a net energy transfer from the tumor stroma to epithelial cancer cells (an energy imbalance), thereby promoting tumor growth. This net energy transfer is both unilateral and vectorial, from the tumor stroma to the epithelial cancer cells, representing a true host-parasite relationship. We have termed this new paradigm “The Autophagic Tumor Stroma Model of Cancer Cell Metabolism” or “Battery-Operated Tumor Growth”. In this sense, autophagy in the tumor stroma serves as a “battery” to fuel tumor growth, progression, and metastasis, independently of angiogenesis. Using this model, the systemic induction of autophagy will prevent epithelial cancer cells from using recycled nutrients, while the systemic inhibiton of autophagy will prevent stromal cells from producing recycled nutrients—both effectively “starving” cancer cells. We discuss the idea that tumor cells could become resistant to the systemic induction of autophagy, by the up-regulation of natural endogenous autophagy inhibitors in cancer cells. Alternatively, tumor cells could also become resistant to the systemic induction of autophagy, by the genetic silencing/deletion of pro-autophagic molecules, such as Beclin1. If autophagy resistance develops in cancer cells, then the systemic inhibition of autophagy would provide a therapeutic solution to this type of drug resistance, as it would still target autophagy in the tumor stroma. As such, an anti-cancer therapy that combines the alternating use of both autophagy promoters and autophagy inhibitors would be expected to prevent the onset of drug resistance. We also discuss why anti-angiogenic therapy has been found to promote tumor recurrence, progression, and metastasis. More specifically, anti-angiogenic therapy would induce autophagy in the tumor stroma via the induction of stromal hypoxia, thereby converting a non-aggressive tumor type to a “lethal” aggressive tumor phenotype. Thus, uncoupling the metabolic parasitic relationship between cancer cells and an autophagic tumor stroma may hold great promise for anti-cancer therapy. Finally, we believe that autophagy in the tumor stroma is the local microscopic counterpart of systemic wasting (cancer-associated cachexia), which is associated with advanced and metastatic cancers. Cachexia in cancer patients is not due to decreased energy intake, but instead involves an increased basal metabolic rate and increased energy expenditures, resulting in a negative energy balance. Importantly, when tumors were surgically excised, this increased metabolic rate returned to normal levels. This view of cachexia, resulting in energy transfer to the tumor, is consistent with our hypothesis. So, cancer-associated cachexia may start locally as stromal autophagy, and then spread systemically. As such, stromal autophagy may be the requisite precursor of systemic cancer-associated cachexia.     

Intratumoral bacteria are an important “accomplice” in tumor development and metastasis

As emerging tumor components, intratumoral bacteria have been found in many solid tumors. Several studies have demonstrated that different cancer subtypes have distinct microbial compositions, and mechanistic studies have shown that intratumoral bacteria may promote cancer initiation and progression through DNA damage, epigenetic modification, inflammatory responses, modulation of host immunity and activation of oncogenes or oncogenic pathways. Moreover, intratumoral bacteria have been shown to modulate tumor metastasis and chemotherapy response. A better understanding of the tumor microenvironment and its associated microbiota will facilitate the design of new metabolically engineered species, opening up a new era of intratumoral bacteria-based cancer therapy. However, many questions remain to be resolved, such as where intratumoral bacteria originate and whether there is a direct causal relationship between intratumoral bacteria and tumor susceptibility. In addition, suitable preclinical models and more advanced detection techniques are crucial for studying the biological functions of intratumoral bacteria. In this review, we summarize the complicated role of intratumoral bacteria in the regulation of cancer development and metastasis and discuss their carcinogenic mechanisms and potential therapeutic aspects.     

CPT2 down-regulation promotes tumor growth and metastasis through inducing ROS/NFκB pathway in ovarian cancer

BackgroundCarnitine palmitoyltransferase 2 (CPT2) is a rate-limiting enzyme involved in fatty acid β-oxidation (FAO) regulation. Recently, it has been increasingly recognized that lipid metabolism dysregulation is closely implicated in tumorigenesis. However, the involvement of CPT2 in the progression of cancer is still largely unclear, especially in ovarian cancer (OC).MethodsIn the present study, CPT2 expression and its clinical significance were determined in OC tissues and cells. The biological functions and molecular mechanisms of CPT2 in OC growth and metastasis were determined by in vitro and in vivo assays.FindingsWe found that CPT2 was frequently down-regulated in primary ovarian serous carcinomas, which is significantly correlated with poor survival of ovarian cancer patients. Functional experiments revealed that CPT2 inhibited OC cell growth and metastasis via suppression of G1/S cell cycle transition and epithelial to mesenchymal transition (EMT), as well as induction of cell apoptosis. Mechanistically, suppression of ROS/NFκB signaling pathway by increasing fatty acid oxidation-derived NADPH production was involved in the anti-tumorigenic functions of CPT2 in OC cells.InterpretationAltogether, our findings demonstrate that CPT2 functions as a potential tumor suppressor in OC progression. CPT2 may serve as a novel prognostic marker and therapeutic target in OC.     

miR-29b suppresses tumor growth and metastasis in colorectal cancer via downregulating Tiam1 expression and inhibiting epithelial–mesenchymal transition

Recently, the role of miR-29b in colorectal carcinoma (CRC) development appears to be controversial. Until now, the expression and function of miR-29b in CRC have not been clarified clearly. We showed that decreased expression of miR-29b usually occurred in CRC cell lines and tissue samples. Loss- and gain-of-function assays in vitro revealed suppressive effects of miR-29b on cell proliferation and migration. Endogenous overexpression of miR-29b was sufficient to suppress aggressive behavioral phenotypes in mice. Proteomic analysis showed that miR-29b involved in integrate several key biological processes. In addition, miR-29b mediated the inhibition of epithelial–mesenchymal transition (EMT) and the inactivation of mitogen-activated protein kinase and phosphatidylinositol-4,5-bisphosphate 3-kinase/AKT signal transduction pathway. Further studies found that T lymphoma invasion and metastasis 1 (Tiam1) was identified as a direct target of miR-29b. In contrast to the phenotypes induced by miR-29b restoration, Tiam1-induced cell proliferation and migration partly rescued miR-29b-mediated biological behaviors. Our results illustrated that miR-29b as a suppressor has a critical role in CRC progression, which suggests its potential role in the molecular therapy of patients with advanced CRC.Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the third leading cause of cancer death. In China, the incidence of CRC is continually increasing despite advances in treatment and subsequent improvement in prognosis. Metastasis leads to most of the mortalities and has a critical role in the poor prognosis.^{1, 2} The underlying molecular mechanisms in CRC metastasis are still unclear. Hence, it is urgent to identify important molecules in cancer progression, which may be used to develop new diagnostic strategies and drugs targeting these markers.MicroRNAs (miRNAs) are a class of diverse, small, noncoding RNAs that are processed from precursors with a characteristic hairpin secondary structure.³ They usually function as critical gene regulators. In recent years, a large number of studies have confirmed that miRNAs have important roles in tumorigenesis and metastasis by targeting different mRNAs.⁴ To date, abnormal expression of several miRNAs, such as miR-21,⁵ miR-124,⁶ miR-625,⁷ miR-339-5p⁸ and miR-27b,⁹ has been identified in CRC and may contribute to the development and progression of CRC. In our recent study, miR-133a was identified as a tumor-suppressive miRNA in human CRC that acts by repressing LIM and SH3 protein 1, which has been previously identified as tumor metastasis-associated protein,¹⁰ provides additional evidence of a pivotal role for miRNAs in CRC tumorigenesis and progression.¹¹miR-29b belongs to the miR-29b family that comprises three members: miR-29a, -29b and -29c. Recently, several studies have showed that miR-29b was dysregulated and represses tumor progression in hepatocellular,¹² ovarian,¹³ prostate,¹⁴ breast¹⁵ and gastric¹⁶ cancer. In colorectal cancer, increased miR-29b was found in colon cancer cells following exposure to a Hexane extract of American Ginseng (HAG) and suppressed the migration of colon cancer cells.¹⁷ In the other study, increased miR-29b was observed in ulcerative colitis-related CRC compared with ulcerative colitis, suggesting its function as oncogene.¹⁸ Thus, the role of miR-29b in CRC development appears to be controversial. Until now, the expression and function of miR-29b in CRC have not been clarified clearly.In this study, we detected miR-29b expression in CRC cells and tissue samples. Gain- or loss-of-function assays were used to analyze the effect of miR-29b on cell behaviors. We performed xenograft mice models to investigate its therapeutic role in tumor genesis and metastasis in vivo. Finally, we also explored the molecular mechanisms underlying the function of miR-29b and its potential targets.     

Could TCTP contribute to Armin Braun's paradigm of tumor reversion in plants?

Comment on: Brioudes F, et al. Proc Natl Acad Sci USA 2010; 107:16384-9.     

Costimulating epithelial γδ T Cells

Comment on: Witherden DA, et al. Science 2010; 329:1205-10.     

Is (9Z)‐“meso”‐zeaxanthin optically active?

The question raised in the title was answered. (3R, 3'S)-meso-Zeaxanthin was submitted to iodine catalyzed photochemical stereoisomerisation. The enantiomeric (9Z) and (9'Z) geometrical isomers were isolated by semipreparative HPLC and separated as diastereomeric dicarbamates on a chiral column only. Cleavage of the carbamate could not be effected. CD-Spectra of (1"S, 1"S)- and (1"R, 1"R)-dicarbamates of geometrical isomers of (3R, 3'R)- and (3R, 3'S)-meso-zeaxanthin were systematically studied and the contribution from the carbamate moieties revealed. It was concluded that (9Z, 3R, 3'S)-"meso"-zeaxanthin, in spite of having no symmetry elements, is optically inactive. The result has been rationalised in line with the current hypothesis on the origin of carotenoid CD spectra.     

PKCλ/ι signaling promotes triple-negative breast cancer growth and metastasis

Triple-negative breast cancer (TNBC) is a distinct breast cancer subtype defined by the absence of estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor 2 (HER2/neu), and the patients with TNBC are often diagnosed with higher rates of recurrence and metastasis. Because of the absence of ER, PR and HER2/neu expressions, TNBC patients are insensitive to HER2-directed and endocrine therapies available for breast cancer treatment. Here, we report that expression of atypical protein kinase C isoform, PKCλ/ι, significantly increased and activated in all invasive breast cancer (invasive ductal carcinoma or IDC) subtypes including the TNBC subtype. Because of the lack of targeted therapies for TNBC, we choose to study PKCλ/ι signaling as a potential therapeutic target for TNBC. Our observations indicated that PKCλ/ι signaling is highly active during breast cancer invasive progression, and metastatic breast cancers, the advanced stages of breast cancer disease that developed more frequently in TNBC patients, are also characterized with high levels of PKCλ/ι expression and activation. Functional analysis in experimental mouse models revealed that depletion of PKCλ/ι significantly reduces TNBC growth as well as lung metastatic colonization. Furthermore, we have identified a PKCλ/ι-regulated gene signature consisting of 110 genes, which are significantly associated with indolent to invasive progression of human breast cancer and poor prognosis. Mechanistically, cytokines such as TGFβ and IL1β could activate PKCλ/ι signaling in TNBC cells and depletion of PKCλ/ι impairs NF-κB p65 (RelA) nuclear localization. We observed that cytokine-PKCλ/ι-RelA signaling axis, at least in part, involved in modulating gene expression to regulate invasion of TNBC cells. Overall, our results indicate that induction and activation of PKCλ/ι promote TNBC growth, invasion and metastasis. Thus, targeting PKCλ/ι signaling could be a therapeutic option for breast cancer, including the TNBC subtype.Breast cancer is a clinically heterogeneous disease and both intra and inter-tumor heterogeneities provide great challenges for developing successful therapies. Expressions (or absence thereof) of estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor 2 (HER2)/neu are widely used to clinically classify breast tumors into multiple therapeutic groups.¹ The ER/PR-positive and the HER2-positive breast cancer patients could be benefited from endocrine and HER2-targeted therapies.¹ However, triple-negative breast cancers (TNBCs), which represent ∼12–17% of all breast cancer,² lack ER, PR and HER2/neu expressions² and are not responsive to therapies targeting these receptors. Therefore, the only systemic therapy available for TNBC is chemotherapy.³ Furthermore, TNBC is associated with aggressive pathologic features like higher histology grade and mitotic index⁴ and often found to be associated with higher rate of metastasis and recurrence leading to limited clinical outcome.^{5, 6, 7, 8} Recurrence of TNBC tends to recur within a few years after successful initial treatment^{6, 9} and often develops metastasis to the bone, brain and lungs with poor prognosis.^{2, 6} Thus, identification of signaling pathways that regulate malignant progression of breast cancer subtypes, especially TNBCs, would be therapeutically important.In recent years, PKC signaling has been implicated in modulating invasion and metastasis of multiple tumors.^{10, 11} The PKC family consists of multiple serine/threonine kinases and the relative contribution of individual PKC isoforms during cancer progression varies due to pleiotropism.¹² PKC isoforms regulate diverse cellular functions such as cell-cycle regulation, cellular survival, cell–cell communications and apoptosis.¹³ In particular, atypical PKC isoforms, PKCζ and atypical protein kinase C lamda/iota (PKCλ/ι), are known to be important for chemotaxis, cell polarity, migration and wound healing processes.^{14, 15} Aberrations in all these processes are manifested in tumor progression and metastasis.¹⁴ Consistent with these notions, recent studies indicated that atypical PKCs are associated with various human cancers.^{10, 11} Importantly, the PKCλ/ι gene is located at the 3q26.2 genomic region, which is most frequently amplified in human cancer^{16, 17}, and overexpression of PKCλ/ι has been implicated in cancer development in multiple tissues including the lung,^{18, 19} pancreas,²⁰ stomach,²¹ colon,²² esophagus,²³ liver,²⁴ bile duct,²⁵ ovary,¹⁷ prostate²⁶ and brain.²⁷ Recently, few studies have been reported higher expression of PKCλ/ι in ER/PR- and HER-positive breast cancer and also in lymph node metastases.^{28, 29} Kojima et. al.²⁸ showed that PKCλ/ι expression is highly induced in the ER/PR- and HER2-positive IDCs compared with ductal carcinoma in situ (DCIS) and normal breast. PKCλ/ι forms apical-junctional complexes (AJCs) with other polarity proteins such as partitioning defective 3 homolog (PAR3) and partitioning defective 6 homolog (PAR6),^{30, 31, 32, 33} and invasiveness of breast tumor cells was shown to be associated with loss of PKCλ/ι localization from their apical domains.²⁸ In addition, predominant nuclear localization of PKCλ/ι in both normal and atypical ductal hyperplasia (ADH) lesions prompted the concept that PKCλ/ι might be in an inactive state in these lesions.²⁸ However, expression and activation of PKCλ/ι in TNBCs and the functional importance of PKCλ/ι signaling in relation to invasive breast cancer progression and metastasis are very poorly understood.^{10, 11}Here, we studied PKCλ/ι signaling during invasive progression of TNBC. We utilized expression evaluations in triple-negative IDCs as well as metastatic breast cancers of human patients, in vitro and in vivo functional assays, and global gene expression analysis of human patient samples. We concluded that PKCλ/ι signaling is an important regulator for invasion and metastatic progression of human breast cancers including triple-negative subtypes.     

Telomeres and inflammation: Rap1 joins the ends?

Comment on: Teo H, et al. Nat Cell Biol. 2010; 12:758-67.     

Influence of lactose and lactate on growth and β-galactosidase activity of potential probiotic Propionibacterium acidipropionici

Dairy propionibacteria are microorganisms of interest for their role as starters in cheese technology and as well as their functions as probiotics. Previous studies have demonstrated that Propionibacterium acidipropionici metabolize lactose by a β-galactosidase that resists the gastrointestinal transit and the manufacture of a Swiss-type cheese, so that could be considered for their inclusion in a probiotic product assigned to intolerant individuals. In the present work we studied the effect of the sequential addition of lactose and lactate as first or second energy sources on the growth and β-galactosidase activity of P. acidipropionici Q4. The highest β-galactosidase activity was observed in a medium containing only lactate whereas higher final biomass was obtained in a medium with lactose. When lactate was used by this strain as a second energy source, a marked increase of the intracellular pyruvate level was observed, followed by lactate consumption and increase of specific β-galactosidase activity whereas lactose consumption became negligible. On the contrary, when lactose was provided as second energy source, lactic acid stopped to be metabolized, a decrease of the intracellular pyruvate concentration was observed and β-galactosidase activity sharply returned to a value that resembled the observed during the growth on lactose alone. Results suggest that the relative concentration of each substrate in the culture medium and the intracellular pyruvate level were decisive for both the choice of the energetic substrate and the β-galactosidase activity in propionibacteria. This information should be useful to decide the most appropriate vehicle to deliver propionibacteria to the host in order to obtain the highest β-galactosidase activity.