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Review
. 2019 Dec 16:9:1359.
doi: 10.3389/fonc.2019.01359. eCollection 2019.

Ping-Pong-Tumor and Host in Pancreatic Cancer Progression

Wei Mu  1 , Zhe Wang  2 , Margot Zöller  2
Affiliations
Review

Ping-Pong-Tumor and Host in Pancreatic Cancer Progression

Wei Mu et al. Front Oncol. .

Abstract

Metastasis is the main cause of high pancreatic cancer (PaCa) mortality and trials dampening PaCa mortality rates are not satisfying. Tumor progression is driven by the crosstalk between tumor cells, predominantly cancer-initiating cells (CIC), and surrounding cells and tissues as well as distant organs, where tumor-derived extracellular vesicles (TEX) are of major importance. A strong stroma reaction, recruitment of immunosuppressive leukocytes, perineural invasion, and early spread toward the peritoneal cavity, liver, and lung are shared with several epithelial cell-derived cancer, but are most prominent in PaCa. Here, we report on the state of knowledge on the PaCIC markers Tspan8, alpha6beta4, CD44v6, CXCR4, LRP5/6, LRG5, claudin7, EpCAM, and CD133, which all, but at different steps, are engaged in the metastatic cascade, frequently via PaCIC-TEX. This includes the contribution of PaCIC markers to TEX biogenesis, targeting, and uptake. We then discuss PaCa-selective features, where feedback loops between stromal elements and tumor cells, including distorted transcription, signal transduction, and metabolic shifts, establish vicious circles. For the latter particularly pancreatic stellate cells (PSC) are responsible, furnishing PaCa to cope with poor angiogenesis-promoted hypoxia by metabolic shifts and direct nutrient transfer via vesicles. Furthermore, nerves including Schwann cells deliver a large range of tumor cell attracting factors and Schwann cells additionally support PaCa cell survival by signaling receptor binding. PSC, tumor-associated macrophages, and components of the dysplastic stroma contribute to perineural invasion with signaling pathway activation including the cholinergic system. Last, PaCa aggressiveness is strongly assisted by the immune system. Although rich in immune cells, only immunosuppressive cells and factors are recovered in proximity to tumor cells and hamper effector immune cells entering the tumor stroma. Besides a paucity of immunostimulatory factors and receptors, immunosuppressive cytokines, myeloid-derived suppressor cells, regulatory T-cells, and M2 macrophages as well as PSC actively inhibit effector cell activation. This accounts for NK cells of the non-adaptive and cytotoxic T-cells of the adaptive immune system. We anticipate further deciphering the molecular background of these recently unraveled intermingled phenomena may turn most lethal PaCa into a curatively treatable disease.

Keywords: cancer-initiating cell markers; exosomes; immunosuppression; metabolism; metastasis; pancreatic cancer; perineural invasion; stellate cells.

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Figures

Figure 1
Figure 1
Exosome characterization, biogenesis, and targeting. (A) Exosomes are composed of a lipid bilayer, transmembrane protein and the cytoplasm containing proteins, mRNA, non-coding RNA like miRNA and lncRNA and DNA, where PaCIC-TEX, express the CIC markers Tspan8, integrin α6β1/α6β4, CD44v6, CD133, CXCR4, LRP5, EpCAM, and cldn7. Other transmembrane proteins are linked to Exo biogenesis. (B) Exo biogenesis starts with the invagination of membrane microdomains that are characterized by ordered lipids, like low-density lipoprotein, caveolae, clathrin-coated pits, cholesterol-based lipid rafts, and others. (C) After fission and scission of invaginated membrane domains, the EE are guided toward MVB, the traffic differs between the origins from distinct lipid-enriched domains. Most abundant is rab4, rab5, Doa4 promoted migration and invagination into MVB via the ESCRT system. Components of cholesterol-based lipid raft-, TJ-, or TEM-derived EE are not completely explored. Guidance from MVB to the plasma membrane involves rab proteins, phospholipase D, and SNARE. (D) The contact between Exo and target cells can proceed via fusion of the Exo membrane with the cell membrane, by macropinocytosis, receptor ligand binding such as phosphatidylserine binding to TIM4 or MFGE8 or CD166 binding to CD6 or may be facilitated by Exo membrane protein complexes binding to invagination-prone complexes as described for TEM binding to the TCR complex. Exo also bind to the ECM or matricellular proteins, CD44 and integrins being most frequently involved. Full name of proteins are listed in Table S1. In brief, cells use a variety of pathways for the generation of EE, the traffic toward MVB, the loading of ILV with proteins, coding and non-coding RNA and DNA. Exo may preferentially bind to and be taken up by receptor-ligand binding, uptake being facilitated by the engagement of protein complexes at both the Exo and the target cell.
Figure 2
Figure 2
Prominent PaCIC markers. (A) The lead PaCIC marker is CD44v6, a type I transmembrane protein that contributes to the crosstalk with the ECM via its link domain and the HA binding site. It has binding sites for selectins and LRP5/6. The v6 exon product carries binding sites for several growth factors. The cytoplasmic tail has binding sites for ankyrin and ERM proteins including merlin, which promote cytoskeleton association and downstream signaling. (B) Tspan8 is a tetraspanin with a small and a large extracellular loop, the latter mostly accounts for protein-protein interactions. The four transmembrane regions account for intramolecular and intermolecular interactions. The cytoplasmic tail binds PKC and PI4K. Main activities rely on the association with a large range of proteins. Dominant are integrins, but also CD44v6 and an EpCAM-cldn7 complex. (C) Particularly α6β4 is known as a PaCIC marker. Similar to other integrins, it binds matrix proteins, particularly LN. It is a major component of hemidesmosomes anchoring epithelial cells in the basal membrane. Upon activation, it leaves the desmosome complex and associates preferentially with Tspan8. It differs from other integrins by a long cytoplasmic domain of the β4 chain, which promotes multiple signaling pathways. (D) LGR5 is a seven transmembrane protein located close to frizzled. Upon R-spondin binding, it contributes via Wnt activation to ß-catenin liberation. LGR5 activity is supported by CD44v6-associated LRP5/6. (E) CXCR4 is another seven transmembrane protein. This GPCR becomes activated by SDF1 binding. It predominantly signals via trimeric G-proteins. CD44 crosslinking via HA promotes CXCR4 recruitment and strengthens activation of downstream signaling cascades. Activated CXCR4 also associates with Tspan8 (F) Claudin7 is a 4 transmembrane protein, which can be integrated in TJ, where it associates with other claudins, JAM, and occludin and the cytoplasmic zonula occludens proteins. Cldn7 is also recovered outside of TJ. Upon palmitoylation, it associates via a direct protein-protein interaction in the transmembrane region with monomeric EpCAM. The cldn7-EpCAM complex is recruited into TEM and associates with Tspan8. (G) EpCAM is a type I transmembrane protein of many epithelial cells. It forms tetramers, which promote homophilic binding to EpCAM on neighboring cells. It is engaged in signal transduction, predominantly via the liberated cytoplasmic tail that acts as cotranscription factor. (H) CD133 is a five transmembrane protein located in cholesterol-rich membrane domains. It is associated with HDAC6 that stabilizes a ternary CD133-HDAC6-β-catenin complex and β-catenin target activation, which present one of the signaling cascades initiated via CD133. The seven most prominent PaCIC markers belong to distinct protein families and exert non-related functions. Five of these molecules can become recruited into TEM, where they associate via weak, non-protein-protein interactions with Tspan8. This significantly expands the range of activities of TEM and TEM-derived Exo. Of note, all seven CIC markers contribute via different routes to maintain stem cell features.
Figure 3
Figure 3
Tspan8 promoted tumor progression. (A) Tspan8 acts as a facilitator. This accounts for membrane bound Tspan8, where it strengthens CD44v6, integrin, and cldn7palm/EpCAM complex signaling activity via its association with PKC and PI4K. This also holds true for the Exo-recruited TEM complex described to modulate the ECM, to promote or inhibit angiogenesis and to contribute actively to premetastatic niche formation. (B) Tspan8 is associated with MMP14 and the association of Tspan8 with α6β1 promotes, besides other the transcription of MMP2 and MMP9. Upon proform activation, also assisted by the proximity to CD44v6, matrix proteins become degraded and VEGF is released. VEGF, in collaboration with collagen degradation products, promotes angiogenesis. In addition, a complex between Tspan8, CD44v6, α6β4, and MMP is found in focal contact. The matrix degradation promoted tissue injury contributes to platelet activation and thrombosis, where together with the release of VEGF a positive feedback loop is created further pushing platelet activation and thrombus formation. Full name of proteins are listed in Table S1. With the multitude of Tspan8 associating molecules, we only present one example building on the association with MMP, which strengthens angiogenesis and thrombus formation. However, it should at least be mentioned that Tspan8 also associates with TACE, which strongly affect e.g., the delivery of the NOTCH and the EpCAM ICD, both acting as cotranscription factors.
Figure 4
Figure 4
Distinct integrin signaling in PaCIC. (A) Hemidesomosome-integrated α6β4 is associated with BP160/320 and plectin, the complex being linked to intermediate filament. Upon contact with RTK, the β4 cytoplasmic tail becomes phosphorylated, plectin is released from the complex and phosphorylated β4, supported by Tspan8-associated PKC promotes PI3K, MAPK, Rho, and RAC activation. Besides initiating transcription, the complex assists the association with actomyosin and motility. (B) Instead, when α5β1 associates with angiopoietin-activated Tie2, proliferation is initiated via ERK phosphorylation. In the presence of VE-cadherin, linked to actin stress fibers, pMLCK, and pMLC2 collagen fragments initiate actin rearrangement that promotes dissociation of the α5 from the β1 chain, which enclose phosphorylated Tie2. The phosphorylated Tie2 promotes Akt phosphorylation, which supports MYPT1 phosphorylation and MLC2 association that evoke actin rearrangement. Full name of proteins are listed in Table S1. In brief, only parts of integrin-mediated activities are affected by the association with Tspan8. Notably, the same stimulus distinctly affects integrin activation depending on the α or β chain of the integrin.
Figure 5
Figure 5
Multifaceted activities of CD44v6 in PaCIC. (A) Upon HA crosslinking, CD44v6 initiates HAS, uPAR, MMP2, and MMP9 transcriptions, which promote HA assembly and matrix remodeling, where MMP14 contributes to proMMP2 and MMP9 cleavages. (B) CD44v6 can associate with α3β1 such that both molecules jointly contribute to FAK activation and motility. (C) CD44v6 can be cleaved by TACE and subsequently by the presenilin2 complex. The CD44ICD acts as a cotranscription factor, which together with CBP/p300 promotes CD44 transcription (D) By TNFα associating with TGFβRII, EMT protein expression is supported via Smad signaling. The association of CD44v6 with LRP5/6 supports Wnt/frizzled activation such that β-catenin leaves the suppressive complex and acts as cotranscription factor in NOTCH transcription. (E) There are several pathways whereby CD44v6 strengthens PaCIC survival and apoptosis resistance. cMET comes into proximity of CD44v6 via CD44v6-bound HGF. This initiates activation of the PI3K/Akt anti-apoptotic and of the Ras-ERK pathways. In addition, CD44v6 supports cMET transcription. A complex of CD44v6 with HAS, Annexin II, S100A, and activated ERM stabilizes MDR1 expression, which contributes to drug efflux. Finally, stress induces the association with and dephosphorylation of merlin, which attenuates the HIPPO pathway with upregulation of cIAP1/2 and caspace3 cleavage. (F) Some of the multiple activities of CD44v6 in stress protection via affecting the cells metabolism are summarized indicating whether altered metabolism is promoted by signaling cascades in the cytosol or depends on transcriptional activation (red arrows). The latter accounts particularly for β-catenin-TCF/LEF, β-catenin-HIF1α, and β-catenin-CD44ICD complexes, but also for the cooperation of CD44v6 with Tie2, TGFβR1, galectin 9, and BMPR, which affect transcription of a large range of distinct genes. Full name of proteins are listed in Table S1. CD44v6 is engaged in most steps of the metastatic cascade. The strongest impacts are seen in terms of survival, EMT induction and metabolic changes that guarantee unimpaired survival under hypoxic and poor nutrient conditions.
Figure 6
Figure 6
CXCR4 and PaCIC survival and motility. (A) CXCR4 is a G-protein coupled receptor (GPCR) that in PaCa is mostly recovered in association with CD44v6 and/or Tspan8. Activation is initiated by binding of its ligand SDF1. Signals are transferred via the G protein subunits, which promote Ca2+ influx, and either via MAPK or Rho chemotaxis and migration. Chemotaxis and proliferation can also proceed via the Gα, Ras, Raf, pERK1,2 activation route. Activation of PI3K/Akt, Bcl2/pBAD promotes proliferation and survival. The latter is also supported by activation of the STAT-Jak pathway. PI3K/Akt can also initiate activation of transcription factors. Independent of the trimeric G-protein complex, CXCR4 associates with GRK, arrestin and clathrin. The complex becomes internalized, which is accompanied by reduced proliferation and survival. (B) Activation of β-catenin, NFκB and CREB supports transcription of CXCR4, SDF1, Smo, SHH, VEGF, MMP, and Bcl2. These genes are important in PSC activation, recruitment of immunosuppressive MDSC and Treg and the shift of M1 to M2 and in supporting angiogenesis, which may not be dominating in PaCa. Full name of proteins are listed in Table S1. It should be noted that the dominant activity of CXCR4 in promoting chemotaxis and motility covers only one, not essentially dominating feature in PaCIC.
Figure 7
Figure 7
EpCAM, claudin7 and their cooperation in PaCa. (A) In tight junctions, cldn7 is associated with additional cldns, occludin, JAM, and ZO1, 2, and 3, the latter being associated with pMIC2 and the cytoskeleton. Upon stimulation by several cytokine receptors, PI3K, ERK, RhoA/Rock, and MLCK promote MLC2 dephosphorylation, which promotes reorganization of the cytoskeleton with consequences on the cldn associated transporter activity. A stress response provokes internalization of the TJ complex. It is suggested that the internalized complex may be partly digested, recycle and become integrated into Exo. (B) EpCAM form tetramers, which with low affinity bind to EpCAM tetramers on neighboring cells and concomitantly prevent PRKD1 activation that leads to ERK1/2 and myosin activation, which inhibits Ca++-dependent Cadherin adhesion. Alternatively, EpCAM becomes cleaved by TACE and subsequently by PSN2. The cotranscription factor EpICD becomes supported by LEF and ß-catenin that might derive from Kremen1-DKK2-LRP6 promoted Wnt-Frizzled activation. This transcription factor complex mostly supports EpCAM and Wnt target gene expression. (C) Palmitoylated cld7 associates with monomeric EpCAM. As cldn7 is associated with PSN2, EpICD generation is augmented. Palmitoylated cldn7 may also contribute to NICD generation that acts as cotranscription factor. In association with CD44v6 and Tspan8, cldn7palm associates with ERM and contributes to ERM activation and actin binding. In association with uPAR and integrins it promotes both uPAR and integrin activation. Finally, a cldn7Palm-integrin-HSP complex assists talin-FAK-src-RhoA activation and by activation of the Grb2-SOS-RAS pathway ILK and the MAPK-JNK pathway. EpICD, NICD, and ILK contribute to c-myc, cyclinD1 and EMT gene transcription; NICD via HES and c-jun interfere with Pten transcription. Full name of proteins are listed in Table S1. Thus, TJ cldn7 is important particularly in lipid transport and cytoskeleton organization, EpCAM by promoting oncogenes and EMT genes, which also accounts for cldn7Palm-associated EpCAM. Cldn7Palm additionally contributes to Pten silencing.
Figure 8
Figure 8
LGR5 and the contribution to PaCIC maintenance. (A) The leucine-rich repeat-containing GPCR is engaged in Wnt signaling. Its ligand is R-Spondin. In the absence of R-Spondin, the transmembrane E ligases RNF43/ZNRF3 associate with Frizzled and LRP5/6 that leads to Frizzled phosphorylation and internalization of the complex. (B) However, in the presence of R-Spondin, RNF43/ZNRF3 is recruited toward LGR5 such that Wnt can bind to Frizzled and LRP5/6 becomes phosphorylated. Dsh blocks GSK3-β and β-catenin is liberated to move to the nucleus, where it together with TCF/LEF promotes cMyc, cyclinD1, and Axin1 transcription. Full name of proteins are listed in Table S1. The upregulated expression of LGR5 in PaCIC suggests its engagement in PaCIC maintenance.
Figure 9
Figure 9
The core position of pancreatic stellate cells in the dysplastic stroma reaction in PaCa. (A) PSC abundantly contain lipid droplets and lay close to the acinar cells in the healthy pancreas. They become activated by injury or inflammation, with a contribution of inflammatory cytokines, growth factors and ROS. Recurrent injury promotes autokrine signaling with further provision of growth factors, inflammatory cytokines, and chemokines. They partly loose the lipid droplets and become dispersed throughout the pancreatic stroma, where they affect the ECM, PaCa cells, leukocytes, and nerves. (B) Main factors contributing to PSC activation are PDGF and IL33 that assist proliferation and migration, Wnt2-β-catenin and IHH-MMP14 also contribute to the migratory phenotype and IHH-/SHH-Cox2 to proliferation. ELANE-AP1, Wnt2-β-catenin, and Smad3-ERK-TGFß1-Cox2 support collagen secretion, the latter two also support αSMA expression. (C) PSC activation is accompanied by the generation of a very dense ECM rich in HA and collagen, the recruitment of CAF, TAM, MDSC, and Treg, but a paucity of T cells in the dense ECM. Finally, they are engaged in a most intense crosstalk with the PaCa cells. Full name of proteins are listed in Table S1. PSC become activated at an early stage of PaCa initiation. Signals promoting PSC activation contribute to PSC collagen and αSMA expression, proliferation, and migration. aPSC are supposed to account for the ECM formation, to crosstalk with the tumor cells, to recruit and reprogram of leukocytes and to interact with the intrapancreatic nerves, some of these activities are detailed in the following figures.
Figure 10
Figure 10
The crosstalk between PSC and pancreatic cancer cells. (A) Overview of the support provided by aPSC to PaCa survival, expansion and gain in aggressiveness and feedback by the tumor cell, which sustains PSC activation, expansion and matrix protein synthesis. (B) Some of the important components delivered by aPSC toward tumor cells and the initiated changes with a focus on altered metabolism. Glutamate derived from influxed glutamine can replace the TCA cycle to generate citrate, which also can derive from the pyruvate-PDK-Ac-CoA pathway. Lactate, delivered via lactate transporters supports glutamine and glucose generation, GSH upregulation and ROS reduction. Glucose also becomes enriched by glucose transporter in the tumor cell, where PKM2 via NADH and ATP promotes pyruvate generation. After lysosome degradation of aPSC autophagosomes, a plethora of AA, lipids, lipoproteins, sugars, and nucleotides is delivered that in part are taken up by specific receptors, not all being identified so far. Alternatively, autophagosomes are taken up by macropinocytosis, the macropinosome content being delivered after lysosome degradation. Lysosome degradation is also required for the delivery of the aPSC Exo content. Another option is receptor-mediated uptake of selective transmembrane complexes as ANXA6 bound LRP1 and THBS1. The predominant route of transfer from aPSC in PaCa cells is indicated by a color code: red: signaling receptor mediated uptake; blue: delivery or uptake by transporters; vesicle uptake: green; violet: receptor-mediated lipid and lipoprotein uptake; an olive circle encloses for a few of the aPSC-delivered components the pathway, whereby they contribute to the altered metabolism of PaCa cells; others may directly support PaCa survival and aggressiveness. Full name of proteins are listed in Table S1. aPSC support PaCa survival, expansion and progression, which to a considerable degree relies on their input of components initiating energy generation by altered metabolic pathways. Despite the focus on PSC-promoted metabolic adaptation of PaCa cells, the presented data cover only a minor part of the present state of knowledge and additional information can be expected by improved proteomic methodologies combined with organoid cultures.
Figure 11
Figure 11
The nervous system and perineural invasion in pancreatic cancer. (A) Overview of nerve anatomy. The endoneurium surrounds all axons and serves to separate individual nerve fibers. The axons are covered by Schwann cells, where Schwann cells myelinate the axons. Non-myelinating axons mostly ensheath multiple small caliber axons. (B) The anatomy of the pancreatic nerves, neurotrophic factors and receptors as well as growth factors expressed by the engaged cells all contribute to perineural invasion and are supported by adhesion molecules and proteases as demonstrated in (C) for Schwann cells that intercalate between tumor cells promoting destruction of the adhesive matrix and actively recruiting tumor cells toward the nerve by signaling via adhesion molecules that promote cytoskeleton reorganization associated with acquisition of a motile phenotype. (D) Overview of abundantly delivered neurotrophic factors, cytokines, and chemokines by neurons and the corresponding receptors on PaCa tumor cells that promote tumor cell growth and invasion; dominating in the interaction between Schwann cells and tumor cells are L1CAM and NCAM. Besides homophilic binding, they bind integrins and RTK. MAG binding MUC1 on tumor cells mainly contributes to adhesion. For detailed information on signaling cascade initiation in PaCa, please see reviews mentioned in the text file. (E) Besides the direct engagement of neurons, Schwann cells and tumor cells, PSC, TAM, and the dysplastic tumor matrix contribute to PNI. Molecules predominantly contributing to PNI are listed. Selective contributions of aPSC rely predominantly on the transfer of nutrients, Exo and autophagosomes; TAM contribute by the delivery of matricellular proteins like EMAP-II and metabolism regulators such as LDHA and iNOS, the ECM supports PNI by embedded matricellular proteins and proteases. (F) All engaged cell populations are also acceptors of signaling cascade activators such as NGF, axon guidance cytokines/chemokines, and matricellular proteins. Activation of the cholinergic system is of major relevance for nerves and tumor cells. Full name of proteins are listed in Table S1. PNI is one of the dominating pathways of PaCa invasion. It is supported by neurotrophins and neurotransmitters delivered by neurons and Schwann cells, the latter in addition providing guidance factors and membrane integrated proteins that promote adhesion and migration. aPSC are essential in nutrient transfer and TAM provide cue enzymes to cope with ROS and NO. TAM and the ECM contribute by matricellular proteins and proteases that facilitate PaCa cell migration toward the nerve.
Figure 12
Figure 12
The impact of PSC and tumor cells on immune cells in the pancreatic cancer stroma. (A) NK cells in the stroma display reduced activity. This is mainly due to MDSC and Treg that by TGFβ delivery affect TNFα and IFNγ secretion and SMAD3/4 activation, which inhibit GzmB and perforin transcription. The activating NKG2D receptor become deviated toward PSC due to higher expression of MICAB, where MICAB in tumor cells can become shed by ADAM17, free MICAB fragments further deviating NK cells from attacking the tumor cell. The activating receptors NKp46 and NKp30 become downregulated due to a metabolic shift induced by tumor cell derived LDHA and lactate. Activating receptor can also become occupied by inhibitory receptor, like TIGIT. Finally, tumor cells deliver an IgG like molecule, Ighg1, occupying the FcγR of NK cells and thereby interfering with ADCC. (B) PSC have a strong impact on driving Mϕ into TAM by the delivery of IL4, IL10, IL13, mCSF, and glucocorticoids. TAM deliver IL6 and soluble IL6 receptor binding to gp130 on tumor cells, which activates the JAK/Stat3 pathway promoting tumor cell survival and expansion by cyclin, PCNA Bcl2, and Mcl1 expression. TAM also affect the activity of additional immune cells. Lytic NK cell activity becomes inhibited by TGFβ and IP10. A shift of Th1 to Th2 is supported by TGFβ, IL10, CCL22, and Gal1. Expansion and activity of Treg is assisted by TGFβ, IP10, and CCL11. Finally, CTL recruitment, activation and lytic activity are impaired by TAM-derived TGFβ, IL10, IP10, IDO, and Gal1. (C) A central role of TGFβ in immune deviations relies on binding to the TGFβRII, which promotes RAS, PI3K, and TRAF6/4 pathway activation and on TGFβR1 binding, where phosphorylated Smad4 forms a complex with Smad2/3, the complex migrating into the nucleus promoting together with additional coactivators and transcription factor besides other transcription of NOS, PAI-1 and PDGF. (D) CTL activation is prohibited by tumor cells, PSC and immunosuppressive MDSC, Treg and TAM. The major inhibitory factors and membrane molecules are listed. PSC particularly contribute via POSTN, GAL1, SERPINE2, PGE2, and TLR9. Low level MHCI expression on tumor cells hampers CTL activation, high FASL expression contributes to CTL lysis and IDO and PDL1 are inhibitory receptors. As shown in the overview diagram, preventing CTL activation is the result of coordinated activities between all contributing components. Full name of proteins are listed in Table S1. The dense stroma and poor angiogenesis may hamper leukocyte recruitment. However, there is no paucity of immunosuppressive leukocyte, such that changes in metabolism and activation of signaling cascades are dominating immunosuppression. Feedback circles between all contributing elements create a self-replenishing vicious circle.
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