most of the cells in multicellular organisms are surrounded by a complex mixture of nonliving materials that make up the extracellular matrix ( ecm ) . the ecm of vertebrates is composed of complex mixtures of proteins ( collagens , laminins , fibronectin , etc . ) and proteoglycans ( chondroitin sulfate , keratan sulfate , etc . ) ecm plays a significant role in regulating numerous cellular functions , including cell shape , adhesion , migration , proliferation , polarity , differentiation , and apoptosis . in pathological conditions such as cancer , increased synthesis of certain ecm components and/or increased breakdown with consequent generation of ecm cleavage products can contribute to cancer growth and progression . integrins are transmembrane glycoproteins that are composed of a set of noncovalently associated  and  subunits . there are at least 18 and 8 subunits capable of forming more than 24 heterodimers that account for the structural and functional diversity of the integrin family     [ 46 ] . integrins consist of a large extracellular domain , a single transmembrane domain , and a cytoplasmic tail . the extracellular portion of integrins binds to ecm proteins , and the intracellular portion binds to cellular cytoskeletal elements such as actin filaments . the connection also constitutes a signaling platform through which integrins can relay information for major processes such as transcriptional control , cell death , proliferation , and cell migration     [ 8 , 9 ] . there is a growing body of evidence suggesting that alterations in the adhesion properties of neoplastic cells endow them with an invasive and migratory phenotype . indeed , changes in the expression and/or function of integrins have been implicated in all steps of tumor progression , including detachment of tumor cells from the primary site , invasion of ecm , intravasation into the blood stream , dissemination through the circulation , extravasation into distant target organs , and formation of the secondary lesions     [ 5 , 1013 ] . although at least 24 integrin heterodimers are known , 51 , 64 , v3 , and v6 integrins have been extensively studied in cancer and their expression is correlated with cancer progression in various tumor types     [ 1418 ] . upregulation of these integrins renders cancer cells more motile , invasive , and resistant to anticancer drugs     [ 5 , 18 ] . unlike these integrins , expression levels of some integrins , such as 21 and 11 , decrease in tumor cells , which potentially increase tumor cell dissemination     [ 1821 ] . in addition to changes in expression , changes in the function of these integrins also play a critical role in cancer progression . the way in which integrins are trafficked by the endosomal pathway is now recognized to influence their function     [ 6 , 22 ] . certain integrin heterodimers are continually internalized from the plasma membrane into endosomal compartments and subsequently recycled back to the cell surface , which indicates that the endocytic and recycling pathways have the potential to exert minute - to - minute control over integrin function . abundant evidence suggests that integrin trafficking regulates cell adhesion to ecm , establishes and maintains cell polarity , redefines signaling pathways , and controls migration     [ 6 , 23 ] . therefore , transcriptional changes , mutational alterations , and deregulated cellular signaling changing endocytosis and recycling of integrins confer invasive and metastatic properties to tumor cells . integrin trafficking is regulated by members of the ras - associated binding ( rab ) family of small gtpases , which function as molecular switches regulating vesicular transport in eukaryotic cells     [ 24 , 25 ] ( figure 1 ) . through their indirect interactions with coat components , motors , and other proteins , the rab gtpases serve as multifaceted organizers of almost all membrane trafficking processes including integrin trafficking     [ 25 , 26 ] . approximately 70 types of rab gtpases have now been identified in humans . among these , in addition , rab11 mediates slow integrin recycling through recycling endosomes , whereas rab4 mediates fast integrin recycling directly from early endosomes ( figure 1 ) .   the pathophysiological roles of rab gtpases in human malignancies have been less studied compared to members of the ras and rho gtpase families . however , more attention has been paid to the roles of rab gtpases in cancer in recent years , and several members of the rab family such as rab11 and rab25 have been shown to be aberrantly expressed in various cancer types     [ 25 , 28 , 29 ] . because of the important roles of rab gtpases in integrin trafficking , deregulation of rab gtpases is closely related to cancer development and progression     [ 24 , 25 , 29 ] . there are several major endocytosis mechanisms , including clathrin - mediated endocytosis , caveolae - mediated endocytosis , and clathrin- and caveolin - independent endocytosis     [ 3033 ] . clathrin - mediated endocytosis is mediated by small vesicles that have a morphologically characteristic crystalline coat made up of a complex of proteins associated with the cytosolic protein clathrin . clathrin - coated vesicles ( ccvs ) are found in virtually all cells and form domains of the plasma membrane termed clathrin - coated pits . clathrin - coated pits can concentrate large extracellular molecules and receptors responsible for the receptor - mediated endocytosis of ligands , for example , low - density lipoprotein , transferrin , growth factors , and antibodies     [ 30 , 33 ] . in contrast , caveolae - mediated endocytosis is mediated by small flask - shape pits , caveolae , in the membrane . caveolae are the most common reported non - clathrin - coated plasma membrane buds which exist on the surface of many , but not all cell types . they consist of the cholesterol - binding protein caveolin ( vip21 ) with a bilayer enriched in cholesterol and glycolipids . clathrin- and caveolin - independent endocytosis includes macropinocytosis and circular dorsal ruffles     [ 9 , 30 , 33 ] . clathrin - dependent endocytosis and caveolin - dependent endocytosis require dynamin and exhibit small vesicles . like macropinocytosis , circular dorsal ruffles show highly ruffled structures , but this endocytosis is dependent on dynamin . integrins are known to be endocytosed by clathrin - mediated endocytosis , caveolae - mediated endocytosis , and clathrin- and caveolin - independent endocytosis ( table 1 ) . it is probable that a given type of integrin heterodimer follows more than one route to internalization depending on regions within a cell , cell conditions , and cell type     [ 6 , 34 ] . for instance , a subpopulation of integrin 51 is internalized into clathrin - coated structures near focal complexes at the cell front , whereas the bulk of integrin 51 follows a nonclathrin pathway from other parts of the cell surface . deregulation of integrin endocytosis is closely related to cancer development and progression     [ 9 , 30 ] . for example , chromosomal deletion and loss of rab21 , a regulator of endocytic trafficking of integrins , has been found in cancer that leads to the accumulation of multinucleate cells in cancer . the correlation with multinucleate cells is thought to reflect the requirement of rab21-mediated integrin endocytosis for correct cytokinesis     . once internalized , integrins are predominantly recycled back to the plasma membrane , although a fraction of integrin 51 has been shown to traffic to lysosomes for degradation during migration     [ 6 , 37 ] . following endocytosis , integrins travel to early endosomes from which they can either be returned directly to the plasma membrane in a rab4-dependent manner ( the short loop ) or further trafficked to the perinuclear recycling compartment ( pnrc ) before recycling through rab11-dependent mechanisms ( the long loop ) ( table 1 ) . however , the function of the rab11 family member rab25 ( or rab11c ) is controversial . rab25 shows highly restricted expression under normal physiological conditions but is upregulated in invasive cancer cell lines and metastatic tumor cells     , and its elevated expression is further linked to the aggressiveness of breast and ovarian cancers     . rab25 is a determinant of tumor progression , and the aggressiveness of epithelial cancers and is strongly associated with decreased survival     . in contrast , recent studies showed that rab25 expression is decreased in human colon cancers and triple - negative ( negative for estrogen receptor ( er ) , progesterone receptor ( pr ) , and her2/neu ) breast cancers , and rab25 functions as a tumor suppressor in these cancers     [ 4143 ] . the key roles of rab gtpases in tumorigenesis and tumor progression are closely related to integrin recycling . for example , rab25 contributes to tumor progression by directing the localization of integrin - recycling vesicles and thereby enhancing the ability of tumor cells to invade the extracellular matrix     . integrin 51 is a receptor for fibronectin and contributes to cancer cell invasion , metastasis , resistance to anticancer drugs , and decreased survival in patients     [ 17 , 45 ] . integrin 51 is internalized by clathrin - dependent , caveolin - dependent , and clathrin- and caveolin - independent mechanisms . for clathrin - dependent endocytosis , 51 integrin binds to numb , an endocytic protein that influences clathrin - coated pit assembly     . integrin 51 can also internalize with tetraspanin protein , which interacts with ap-2 , an adaptor for clathrin - mediated endocytosis     . clathrin - dependent internalization of 51 integrin with numb or tetraspanin has a profound effect on cell migration . in addition , 51 integrin can undergo rab21- and clathrin - independent endocytosis that is required for successful cytokinesis     . in some cell types , integrin 51 localizes to caveolae for caveolin - mediated endocytosis     [ 6 , 48 ] . internalized integrin 51 is transported through rab4-positive early endosomes and arrives at the rab11-positive perinuclear recycling compartment . akt - mediated glycogen synthase kinase ( gsk)-3 phosphorylation is known to deliver 51 from the rab11 compartment to the plasma membrane     . one of the rab11 effectors , rab11 fip1/rcp , associates with integrin 51 and regulates recycling of this integrin     . rab - coupling protein ( rcp ) provides a scaffold that promotes the physical association and coordinated trafficking of 51 and epidermal growth factor receptor 1 ( egfr1 ) . recently , it was shown that mutant p53 can promote invasion , loss of directionality of migration , and metastatic behavior by regulating the interaction of 51 integrin to rab - coupling protein , which enhances 51 trafficking and signaling     . since rab25 ( rab11c , rab11 family member ) binds to rab11 fip1/rcp , it is hypothesized that interaction between them may control integrin 51 trafficking . recently , it has been shown that rab25 associates with 51 integrin to enhance migration and invasion of cells in three - dimensional microenvironments and directs 51 integrin recycling to dynamic ruffling protrusions at the leading edge of migrating cells , which promotes invasive migration     [ 29 , 44 ] . in addition to rab11 and rab25 , rab21 is required for carcinoma - associated fibroblasts to promote invasion by cancer cells and facilitates integrin 51 accumulation for force - mediated matrix remodeling at the plasma membrane . it has also been shown that rab21-dependent recycling of integrin 51 is critical for proper activation of rhoa during cytokinesis     . although most endocytosed integrin 51 is known to recycle back to plasma membrane , a subset of this integrin moves to lysosomes for degradation     . this process is very slow , but it is important for 51-dependent cell motility     . overexpression of 64 integrin was seen in several types of cancers including breast cancer and correlated with tumor invasion , increased tumor size and grade , and a poor prognosis     [ 5457 ] . we showed that integrin 64 integrin recycles back to the plasma membrane via the rab11-positive perinuclear recycling compartment     . hypoxia stimulated carcinoma invasion by promoting rab11 trafficking of integrin 64 , which is dependent on hypoxia - inhibited glycogen synthase kinase ( gsk)-3 signaling     . integrin v3 is expressed in a variety of tumors such as melanoma , prostate cancer , and breast cancer . integrin v3 is overexpressed in activated endothelial cells during tumor - induced angiogenesis , whereas it is absent on quiescent endothelial cells and normal tissues . it is known that integrin v3 promotes cancer cell survival , migration , invasion , and metastasis     [ 4 , 60 , 61 ] . integrin v3 is endocytosed via clathrin - dependent , caveolin - dependent , or clathrin- and caveolin - independent mechanisms . numb is an alternative clathrin adaptor and can interact with 3 integrin , which controls v3 integrin endocytosis and cell migration     . in some cell types , integrin v3 is internalized by caveolin - dependent mechanisms     . in this case , mt1-mmp is clustered together with caveolin-1 and v3 integrin at motility - associated structures , resulting in increased proteolytic activity , which is important for cell migration and invasion     . a recent study shows that upon growth factors stimulation , integrin 3 abruptly redistributes to circular dorsal ruffles where it is internalized through macropinocytosis , which plays an important role in growth factor - induced cell migration . internalized integrin v3 recycles back to the plasma membrane via rab4-dependent mechanisms or the rab11-positive perinuclear recycling compartment . following treatment with pdgf , integrin v3 was rapidly recycled directly back to the plasma membrane from early endosomes via a rab4-dependent mechanism without the involvement of rab11 . the pkc - related kinase pkd1 influences cell migration by this fast recycling of integrin v3 . it is known that pkd1 directly interacts with 3 integrin and this interaction promotes fast recycling of v3 integrin from recycling endosomes to the plasma membrane upon growth factor stimulation     . activation of vegfr1 also enhances a rab4a - dependent pathway that transports v3-integrin from early endosomes to the plasma membrane . recent studies link pkd and vegf signaling in which vegf - a induces recycling of integrin v3 in a pkd1-dependent manner     . because of the involvement of rab4 in the recycling of v3 integrin , inhibition of rab4 effector protein ( rab ip4 ) blocks integrin recycling , leading to inhibition of cell adhesion and cell spreading . another study suggests that supervillin , an actin and myosin binding protein , regulates rapid 3 integrin recycling through collaboration with rab4 and rab5     . the short - loop recycling of integrin v3 via rab4 does not directly contribute to migration by moving v3 to the cell front , but by antagonizing 51 recycling , which , in turn , influences the cell 's decision to migrate with persistence or to move randomly     . integrin v3 is also recycled to the plasma membrane in a rab11-dependent manner ( long loop recycling ) in which akt promotes this recycling by phosphorylating and inactivating gsk-3     . integrin v6 is usually expressed at low or undetectable levels in most healthy adult epithelia but is upregulated in many cancers such as colon cancer . the expression of integrin v6 inhibits apoptosis and promotes tumor cell invasion and metastasis , which is often associated with a more aggressive disease outcome and a poor prognosis     [ 18 , 70 ] . integrin v6 is internalized by a clathrin - dependent mechanism by interaction with hs1-associated protein x1 ( hax1 )     . hax1 is found in clathrin - coated vesicles , and the cytodomain of 6 integrin interacts with hax1 and is endocytosed , which increases carcinoma migration and invasion     . integrins are key regulators of cell adhesion , migration , and proliferation . therefore , deregulation of their expression and altered functions play critical roles in cancer progression by enhancing cancer cell invasion , metastasis , and survival . there are now clear indications that integrin trafficking is important to modulate integrin distribution and function . however , more studies are needed to define the molecular mechanisms of integrin trafficking in tumor progression . it is known that unligated integrins can positively or negatively regulate tumor cell survival and metastasis , and , therefore , signaling arising from endosomal compartments may be important for tumor cell survival . for instance , it has been shown that rapid recycling of v3 via the rab4 pathway antagonizes the rab11-mediated 51 recycling , which influences the cell 's decision to migrate with persistence or to move randomly     . because of the critical roles of integrins in cancer progression , integrins are potential targets for the development of targeted anticancer therapeutics . understanding the mechanism of integrin trafficking will provide valuable information for the development of new anticancer drugs and clues to increase the efficacy of current anticancer therapeutics .