Keywords: Cell; Caveolae; Extracellular; Invaginations; Intracellular; Plasma membrane
Caveolae (plasmalemmal vesicles) were first identified in 1953-1955 as endocytic structures that transport molecules across endothelial cells [2]. In Latin "Caveolae" means "little caves", which are small plasma membrane lipid rafts of 50 - 100 nanometer in size and was discovered by electron microscopy in 1953. Under transmission electron microscopy, it appeared as flask-shaped plasma membrane invaginations of strikingly regular shape and size (≈ 70 nm average outer diameter) that lack a membrane dense coat. The caveolae are present in most of the cells but are predominant in terminally differentiated mesenchymal cells including endothelial cells, vascular smooth muscle cells, adipocytes, fibroblasts, type I pneumocytes of the lung and striated muscle cells [3,4,5].
Caveolin (Cav) and Cavin are the key protein components of caveolae which are supplemented in glycosphingolipids and cholesterol. Caveolins are proteins closely associated with caveolae and are also known as Cav - 1 or VIP21 (Vesicular Integral-membrane Protein of 21kDa). VIP21 was cloned as component of the vesicular transport machinery localized at the plasma membrane, Golgi bodies and on vesicular structures [6,7]. Cav -1 was the first member of caveolin family to be identified as a tyrosine-phosphorylated protein in cells transformed by the Rous sarcoma virus. In mammals, three caveolin genes are expressed (caveolin 1, caveolin 2, caveolin 3) and it codes for 4 protein isoforms (caveolin- 1α, caveolin- 1β, caveolin 2 and caveolin 3). Most of the body tissues express at least one of these isoforms. Caveolin - 1 high level expression was observed in adipocytes, fibroblasts, endothelial cells, smooth muscle cells and type 1 pneumocytes. Caveolin - 2 expressions was observed with caveolin - 1 for membrane localization and stability whereas caveolin - 3 was predominantly expressed in heart and skeletal muscle cells. So, among these three caveolins, only Cav 1 and Cav 3 are required for the caveolae biogenesis. Monier, et al. showed high affinity of Cav 1 for cholesterol which helps it to form oligomer and this Cav 1 oligomerization is a key feature for the formation of complete caveolae structure [8].
Cavins are other heteromeric protein complexes that are recruited to the caveolae. Four Cavins are identified so far in mammals these includes Cavin 1/PTRF(Polymerase I and Transcript Release Factor), Cavin 2/SPDR (Serum Deprivation Response Protein), Cavin 3/SRBC (Sdr-Related Gene Product That Binds To C-Kinase) & Cavin 4/MURC (Muscle – Restricted Coiled - Coil Protein) [9].
Hansen CG, et al. identified two new caveolar proteins namely EDH2 protein and Pacsin2/syndapin-11. EDH2, an ATPase, does not form caveolae but helps in its stabilization at the membrane site and is present in the neck of caveolae. Any defect either increase or decrease of EDH2 will directly affect the endocytosis function brought about by caveolae. Pacsin 2 plays its role in morphogenesis by localizing itself partially with caveolae through a membrane curvature binding domain (BAR). Alterations in pascin 2 results in altered morphology of caveolae thereby causing decrease in Cav 1 and cavin proteins [14,15,16].
Cytoskeletons of the cell like actin filaments, intermediate filaments and microtubules, are all associated with caveolae. Caveolaes involves them in intracellular signaling by uniting signaling boards at the cell membrane. It has been showed that these caveolaes have been involved in several signaling pathways such as MAPK (Mitogen Activated Protein Kinase), AKT/PKB (Protein kinase B), Src Kinases (sarcoma family kinases), Rho and Rac 1 GTPase.
Studies on caveolins function have opened a door for some of the proposed hypothesis like caveolin scaffolding domain hypothesis and caveolae signaling hypothesis. These hypotheses were in support to understand the apparent diverse function of Cav 1 & Cav 1 interacting molecules. Recently, Lamaze C and Torrino S proposed new hypothesis "mechano-dependent caveolae disassembly/reassembly" [20].
Cav 1 modulates signal transduction at the scaffolding region through an interaction with lipids mainly cholesterol. Experimental studies and genetic evidences have shown Cav 1 importance in maintaining caveolae cholesterol levels. It functions to maintain the caveolae lipid scaffold by replacing oxidized cholesterol with the new cholesterol. Hence, in caveolae scaffolding domain hypothesis caveolae lipid itself form a scaffold that systematizes multiple signaling molecules and controls their interactions.
Smart E, et al. in 1996 [33] strongly suggested that caveolin 1 plays a role in import and export of cellular cholesterol. He observed that in normal human fibroblasts cholesterol moves directly to the plasma membrane after being synthesized in the endoplasmic reticulum and then to the extracellular space. Plasma membrane cholesterol can also move directly to the endoplasmic reticulum. Graf GA in 1999, [34] showed binding of SR-B1 (Scavanger receptor class B membrane 1) to free cholesterol, cholesterol esters and cholesterol ethers in High Density Lipoproteins (HDL) which allows their movement to the intracellular sites from caveolae. Caveolin 1 is also present in the cytosol of many cells, where it gets associated with the cholesterol and behaves like a protein that is embedded in a particle with the size and light density of HDL. Ito J, et al. [35] showed that apoA-1(apolipoprotein A 1) binding to SR-B1 which stimulates the formation of cytosolic lipid particle containing caveolin 1,cholesterol and phospholipid. Hence, both intracellular and extracellular lipid transport function is carried out by caveolin 1 Figure 1 & 2.
Membrane trafficking takes place at the caveola where caveolin 1 attracts proteins and functions as molecular engine that powers membrane invagination and budding. The exact way by which caveolin 1 performs this function is not known but the little evidence suggests its interaction with several tyrosine kinases and EGFR (Epidermal Growth Factor Receptor). Li PU, et al. [36] challenged the role of caveolin 1 in caveolae internalization and suggested that the Autocrine Motility Factor (AMF) is transported through caveolae pathway directly to the Endoplasmic Reticulum (ER) without the involvement of caveolin 1 and this delivery of AMF to ER is 5 times faster than the
A variety of mechanisms have been recommended to elucidate how caveolin-1 may stimulate tumorigenesis. In prostate cancer cells, increased caveolin-1 levels were found to favor growth factor release and regulation by a positive feedback loop that enhances tumor cell invasiveness [48] and VEGF-associated angiogenic signaling [49]. In breast cancer cells, caveolin-1 was shown to associate with type 1 matrix metalloproteinase, thereby promoting invadopodia formation and matrix degradation, and this provides a mechanism for increased invasiveness [50]. Successful tumor cell migration requires proper cell polarization, directionality, and the ability to invade new surrounding matrices and cav 1 is one among them, proved in different experimental research studies [51,52].
Cav 1 which is highly expressed in endothelial cells is down regulated during the proliferative phase and up regulated during the differentiation phase of angiogenesis. In transmigrating endothelial cells, caveolin-1 was shown to interact with intermediate filaments [53]. In provision to this, an evidence involves caveolin-1 in regulating the small GTPases Rho and Rac, which are required for actin dynamics, cell polarization, and directional migration [54,55,56]. The role of caveolin-1 in tumorigenesis is not limited only on mechanisms of migration and invasiveness. But it was associated with various expression linked to the attainment of qualities associated with malignant cell behavior, including Multidrug Resistance (MDR) and metastasis, as well as poor prognosis.
The caveolin-1 plays a dual role in cancer. The uncertainty of caveolin-1 function is best resolved by the model for colon cancer. Early on the cellular environment, caveolin-1 is reexpressed, it develops traits consistent with a role as a tumor suppressor. Regulation of the Wnt signaling pathway is depicted as one of the possibility. Caveolin-1 into tumor cells that still express E-cadherin leads to the repression of beta - catenin- Tcf/Lef-dependent transcription of genes, such as cyclin D1, cox-2, survivin and c-myc. However, during tumor progression multiple changes occur at the molecular level (i.e., genome instability, genetic mutations and/or epigenetic alterations). One such possibility is the loss of E-cadherin. In this situation of cellular environment, caveolin-1 can no longer repress pathways associated with its role as a tumor suppressor. Instead, traits of the molecule prevail that favor the development of Multi-Drug Resistance (MDR) and metastasis. Therefore, it was suggested that caveolin-1 is a "conditional" tumor suppressor and that its ability to promote or suppress tumor development depend both on the cellular context and environmental conditions [57] Figure 4.
Various treatments can enhance the ability of fibroblasts to stimulate tumor cell invasion which include irradiation [63] and reactive oxygen species [64,65,66] as well as lifestyle-correlated factors, such as cigarette, smoke [67] and areca nut extract [68]. Fibroblasts have also been shown to encourage tumor cell invasion through secretion of a number of factors, including chemokine (C- C motif) ligand 2, stromal cell-derived factor-1, TGFb, IL-33, MMP2, EGFR ligands, and Hepatocyte Growth Factor (HGF).
Tkachenko E, et al. showed that in prostate cancer Cav 1 stimulate specific angiogenic activities through the modulation of P13K-eNOS (Phosphatidylinositol 3-Kinase-endothelium nitric oxide synthase) pathway [77]. NO (Nitric Oxide) was discovered by Furchgott and Zawadzki as "Endothelium-Derived Relaxing Factor" (EDRF). It soon became obvious that EDRF, like nitroglycerine, activates soluble guanylate cyclase in vascular smooth muscle by binding to its active haeme centre. The three NOS isoenzymes (neuronal, endothelial and inducible) and among all eNOS is responsible for maintaining low vascular tone and preventing leukocytes and platelets from adhering to the vascular wall [57] Table 1.
Caveolae role in inflammation was partly explained by the "Caveolae Signaling Hypothesis". Antibacterial response of neutrophils can be induced by activation of the NADPH oxidase,
NOS Isoenzymes |
eNOS |
nNOS |
iNOS |
Originally cloned |
Endothelial cells |
Neuronal cells |
Macrophages |
Gene encoding and its position |
NOS3 7q35-36 |
NOS1 12q24.2-31
|
NOS2 17q11.2-12 |
Major regulatory mechanism
|
Ca+2 dependent (Ca-calmodulin) Ca+2 independent (phosphorylation, palmitoylation) |
Ca+2 dependent (Ca-dystrophin)
|
Ca+2 independent; transcriptional regulation e.g. by NFB |
Subcellular localisation
|
Golgi apparatus plasmalemmal caveolae |
Cytosol endoplasmic reticulum sarcollema postsynaptic densities caveolae (caveolin 3) |
Phagosomes |
Keap1-Nrf2 system, as a key signaling pathway that regulates transcription of a series of cytoprotective proteins, plays an important role in oxidative stress, inflammation and carcinogenesis [87]. Keap1 is essential for the regulation of Nrf2 activity; both of them enhanced proliferation, drug resistance and could be potent survival factors in cancers [88]. The strong correlations were observed between caveolin-1 expression and Keap1-Nrf2 system suggesting that caveolin-1 play important role together with Keap1-Nrf2 system in the progression of OSCC.
Gould ML, et al. and Low JY, et al. observed loss of cavin1 expression during the progression of prostate cancer. This down regulation resulted in cell migration, tumor progression and metastasis. All these events occur through the reduce expression of matrix metalloproteases and altered secretion of enzymes, cytokines and growth regulatory proteins. Cavin 1 expression is also decreased in number of cancers like lung cancer and breast cancer, cavin 2 is down regulated in breast, kidney and prostate cancers as well whereas cavin 3 is down regulated in ovarian cancers and breast cancers. Cavin 1 and Cav 1 are cotranscriptionally regulated to modulate oncogenic function and to enhance aggressiveness. [20]
In colon cancer, the established Wnt signaling pathway became one of the attractive potential caveolin-1 targets. This was substantiated by reports by Hulit, Bash, et al. 2000, on one hand caveolin-1 expression prevented transcription of cyclinD1 by sequestering β catenin and on the other hand survivin is a β catenin/Tcf/lef target gene [89]. Hence, assuming these roles the authors recognized that caveolin-1 controlled survivin expression by sequestering β catenin at the plasma membrane [90]. Subsequently this ability required the expression of E-cadherin in colon cancer and melanoma cell lines [91]. Lobos-González L, et al. suggested that the combined loss of caveolin-1 and E-cadherin in epithelial cells is likely to promote increased expression of genes relevant to epithelial-mesenchymal transition, loss of cellcell contacts and cell transformation [92] Table 2.
|
Caveolin - 1 expression |
||||
Tissue affected |
Normal |
Cancer – early phase |
Cancer – late phase |
In vivo study |
In Vitro study |
Colon cancer |
High expression |
Low expression |
Metastasis |
Increased susceptibility to tumors |
Not available |
Breast cancer |
High expression |
Low expression |
Metastasis |
Increased susceptibility to tumors |
High susceptibility to chemotherapy; Invadopodia |
Lung |
High expression |
Low expression |
Metastasis |
Hyperplasia |
Cell polarization and migration |
Melanoma |
Not known |
Not known |
Metastasis |
Not known |
Not known |
Oral Squamous Cell Carcinoma |
High expression |
Low expression |
Metastasis |
Not known |
Not known |
The odontogenic cystic lesions extensively expressed Cav 1 in the basal cell layer showing both membrane and cytoplasmic staining whereas few odontogenic tumors showed immunoreactivity to a smaller degree and more focally. This suggested that cav-1 could be a tumor suppressor in odontogenic tumors. Jaafari-Ashkavandi Z, et al. [96] demonstrated immunoreaction of cav 1 in the basal cells of cysts and tumors, and reported that this marker is not related to proliferation activity. Various researches have been studied on the expression of proliferation markers (such as Ki-67) in odontogenic cysts and tumors which reported higher proliferative activity in tumors compared to cysts [97].
Expression of cav-1 has been reported in enamel organ, particularly inner enamel epithelium and ameloblast cells of developing tooth germ [95]. It was also demonstrated that cav-1 participated in cell transformation and differentiation [98]. But the immunoreaction of cav 1 appeared clearly in less differentiated cells of cysts and tumors (basal cells, ameloblast-like and some stellate reticulum- like cells) and not in differentiated superficial cells of odontogenic cysts and tumors. So, it is hypothesized that cav-1 may be a useful marker for differential diagnosis of odontogenic lesions [96].
Cohen AW, et al. observed down regulated expression of cav 1 which could be due to transcriptional silencing through hypermethylation of the caveolin 1 gene promoter, which further, may nullify cav 1 expression in human cancers. They observed the down regulation of cav 1 in advanced stage, high grade malignancy or those tumors that had longer duration compared with tumors that had shorter duration. This feature indicates the tumor suppressor activity of cav 1 [99].
Hoffman R in 2004, hypothesized that, in the quiescent vasculature, many factors that regulate angiogenesis normally are held together as part of an inactive modular unit (termed as Angosome); and when, angiogenesis is stimulated, the angosome dissociates, thus enabling angiogenic regulators to become active. It is proposed that angosome is present in the caveolae of capillary endothelial cells. The presence of caveolin 1 can inhibit proangiogenic factors. It may act as a master-switch, coordinating events during angiogenesis. This was further supported by Liu J, et al. [100] that angiogenesis activators such as VEGF, basic fibroblastic growth factor and hepatocyte growth factor, down regulate cav 1 in endothelial cells and the down regulation of cav 1 may be an important step along the pathway toward endothelial cell proliferation.
Cav 1 was identified as a metastasis associated gene that is a transcriptional target of EWS/FLI1 (Ewing's sarcoma / friend leukemia integration 1 transcription factor) as well as an important determinant of ESFT (Ewing's sarcoma family of tumors) malignant phenotype and tumorigenicity [104]. Sáinz- Jaspeado M, et al. [105] showed that Cav 1 knockdown led to up regulation of Snail and the concomitant loss of e-cadherin expression. Consistently, loss of Cav1 expression inhibited the anchorage-independent growth of EWS cells and markedly reduced the growth of Ewing's sarcoma cell-derived tumors in nude mice xenografts, indicating that Cav 1 promotes the malignant phenotype in Ewing's sarcoma carcinogenesis. They demonstrated that CAV1 controls migration and invasion in ESFT cells in culture by mechanisms involving the production and activation of metalloproteinases In another study Cav1 expression determines the sensitivity of ESFT cells to clinically relevant chemotherapeutic agents [106].
Cantiani L, et al. demonstrated that cav1 act as an oncosuppressor in human osteosarcoma. The down-regulation of cav 1, is the part of osteoblast transformation and osteosarcoma progression [107]. The 6-year follow-up resulted in a better overall survival for osteosarcoma expressing a level of Cav1. Moreover, the majority of primary osteosarcoma showed significantly lower levels of Cav1 than normal osteoblasts suggesting its role as an oncosuppressor. Mayordomo E, et al.
carried out both in vitro and in vivo study but could not able to conclude that cav 1 is a marker either for good or for bad prognosis. In his, in vitro study, osteosarcoma cell lines forced to over express cav 1, which showed reduced malignancy with inhibited anchorage-independent growth, migration and invasion whereas in vivo study, cav 1 over expression nullified the metastatic ability of osteosarcoma cells. They also showed that c-Src and c-Met tyrosine kinases, which are activated in osteosarcoma, co-localized with cav 1 and were inhibited upon cav 1 over expression [108].
Cav 1 and Caveolin-3, both are expressed specifically in muscle tissue. Cav1 restrict its expression to satellite cells (represents a pool of quiescent reserve elements) whereas Cav 3 expresses in myoblast cells undergoing differentiation and in mature fibers. [109, 110] This suggests that timely coordination of Cav1 and Cav3, contributes to skeletal muscle homeostasis. In skeletal muscle sarcoma, Cav3 is considered a sensitive and specific marker [111] and Cav1 is considered a marker of poor differentiation [112] associating its expression to a better prognostic entity. Hence, depending on the varied role of Cav1 in sarcomas, it may be possible to use different targeting options. For example, the sarcomas in which Cav1 act as a tumor suppressor; either a targeted ectopic re-expression or introduction of a CSD (Caveolin Scaffolding Domain) would be a viable option. Also, cases where Cav1 acts as an oncogene, a direct targeting of Cav1 using antisense or indirectly by chemical inhibition, or lowering cholesterol (that disrupts caveolae) may be of great help [113, 114].
Caveolin expression has also been defined in a variety of vascular neoplasms, including capillary hemangiomas, targetoid hemosiderotic hemangiomas, tufted angiomas, angiosarcomas, Kaposi's sarcoma, and epithelioid hemangioendotheliomas [116]. Bayer-Garner I, et al. studied immunohistochemical analysis of the scaffolding protein caveolin but failed to discriminate among benign and well-differentiated smooth muscle and adipocyte neoplasms. He observed Caveolin immunostaining in both the nucleus and cytoplasm of cells of mesenchymal tumors, including the adipocyte of all types of lipoma and welldifferentiated liposarcoma, the myocyte of angiomyolipoma, leiomyoma, and well-differentiated leiomyosarcoma whereas all the poorly differentiated and dedifferentiated sarcoma, including leiomyosarcoma and liposarcoma, showed weak immunoreactivity or failed to stain with caveolin. So, these observations presented some important pathogenic implications [117].
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