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Normal cells continuously monitor the nature of their respective cellular microenvironment. They are equipped with an inherent molecular defense to detect changes which can precipitate and trigger an oncogenic cascade in the internal and external environment of cells. The process called Anoikis unleashes many a characteristic molecular changes in cells which eventually program to cell death in response to cell detachment and inappropriate cellular attachment, both of which can otherwise potentiate the ability of cells to preferentially pursue a malignant course due to release of molecular discipline which conforms them to a benign structural and functional spectrum. The initiation and propagation of signaling which serves as a switch to cell survival or cell death mediated by surveillance of cell microenvironment is comprised of many heterogeneous sets of molecules interacting mainly at the interface of cell-extracellular matrix. Transforming cells continuously reprogram their signaling characteristics in sensing and modulating the stimuli from cell surface molecules like integrins, cadherins and immunoglobulin family of cell adhesion molecules at adhesion complexes which enables them to resist anoikis and metastasize to different organs. Actin cytoskeleton binds BIM and BMF which are regulated by the adhesion status and consequent conformation of cytoskeleton in the cells. This review aims at an integrated synopsis of fundamental mechanisms of the critical interactions of cell surface molecules to facilitate a focused analysis of differential regulation of signaling processes at cell-ECM junctions that collectively rein the anoikis resistance which in turn impacts metastatic aggressiveness and drug-resistance of tumors originating from respective organs.
Anoikis is defined as the apoptosis of the cells induced by inadequate or inappropriate cell-matrix interactions. Anoikis is a Greek term, meaning “Homelessness” or “Loss of home”. It was first defined by Steven M Frisch (1). It is involved in a diversity of tissue oncogenic, homeostatic and developmental processes. The extracellular matrix (ECM) is under continuous cellular surveillance in order to monitor the positioning of newly dividing normal cells to the designated anatomical context of tissues and to direct cells, which acquire invasive and migratory phenotype, towards programmed cell death (2). The primary regulators of anoikis are naturally localized to cell-ECM junctions due to the presence of “molecules sensed” in ECM and the presence of “molecular sensors” at the cell membrane. The task of anoikis mediated cell surveillance is accomplished by a diversity of ligands in the extra cellular matrix, cell adhesion molecules, integrins, and cytoplasmic cell adhesion complexes which initiate signals that eventually rein the mitogenic and apoptotic signaling cascades to generate either net survival and proliferative signal in normal cell environment or net apoptotic signal in the context of abnormal cell environment. Thus, the principal inputs of anoikis are derived from the interaction and surveillance of cell-ECM contacts which consequently impact the rate of growth and pattern of differentiation of cells.
Anoikis resistance is a natural molecular prerequisite for aggressive metastatic spread of cancers as local invasion and distant colonization require survival in inappropriate extracellular environment where as hematogenous and lymphatic dissemination of tumor cells requires the ability to thrive in de-adherent states. Many signaling molecules that are over expressed in tumors have well defined impact on anoikis. The tropomyosin related kinase B (TrkB) is frequently over-expressed in many aggressive gastric and prostate carcinomas (3–5). TrkB over-expression also induces resistance to doxorubicin, etoposide and cisplatin in neuroblastoma cells (6). In a classical study, in order to examine the impact of TrkB on anoikis resistance, Douma et al transfected highly anoikis sensitive rat intestinal epithelial cells with TrkB which lead to the formation of multi-cellular spheroids in suspension, a distinct characteristic of acquisition of anoikis resistance (7).
Epithelial Mesenchymal Transformation (EMT) plays a vital role in anoikis. The transformation of epithelial cells to mesenchymal phenotype during the progression of tumors not only influences cellular phenotype, but also causes substantial changes in the extracellular matrix that enhance cell proliferation and invasion. During EMT, there is increased availability of growth factors like insulin growth factor (IGF), increased levels of fibronectin, vimentin and membrane metaloproteases (MMPs) along with increased vascularity which collectively enhance tumor survival and progression (8–11). Transfection of mesenchyme specific periostin gene into tumorigenic but non metastatic 293T epithelial cells lead to mesenchymal phenotype and increased invasion and migration (12). The conversion to mesenchymal phenotype is associated with increased drug-resistance in ovarian cancers (13). Loss of epithelial markers in breast cancers is associated with adriamycin and vinblastine resistance (14). Even with advancing multi-disciplinary cancer care, pancreatic cancer is one of the most lethal tumors associated with highly malignant course and poor prognosis with only 6.9% survival at 12 months and 6.4% survival at 5 years of diagnosis (15). Gene expression profiling of pancreatic carcinoma cells resistant to three chemotherapy agents, gemcitabine, 5-fluorouracil (5-FU), and cisplatin, unveiled that the drug-resistant cells had increased expression of genes that favor mesenchymal phenotype that was specifically associated with the over-expression of zinc finger E-box binding homeobox 1 (zeb-1), an E-cadherin repressor (16). Another separate study on gemcitabine resistant pancreatic cancer cells revealed notch signaling induced enhanced expression of snail homolog 1 (SNAIL) and survival of motor neuron protein interacting protein 1 (SIP1) along with other EMT inducing genes (17).
SNAIL is a zinc finger family transcriptional repressor, which is over expressed in high-grade primary human breast carcinomas and lymph node positive breast tumors (18). The expression of SNAIL is highly associated with a switch to mesenchymal phenotype in epithelial cells. Yeast one hybrid analysis of SNAIL binding has revealed that it binds through the amino terminal SNAG (SNAIL or growth factor independent domain) to the SIN 3A co repressor complex containing histone deacytylase, which in turn inactivates chromatin and inhibits the transcription of epithelial marker E-cadherin to induce a mesenchymal phenotype (19). The enhanced survival in matrix deprivation due to SNAIL is via activation of PI3K. Phosphorylated PI3K inactivates pro-apoptotic BCL-2 family member BAD through AKT and ERK (20). Activated ERK phosphorylates pro-apoptotic BIM and marks it for ubiquitin mediated proteasomal degradation. The function of SNAIL is enhanced by IGF signaling which phosphorylates and inactivates glycogen synthase Kinase 3 beta (GSK3B), an inhibitor of SNAIL (21).
SIP 1(Smad interacting protein) is another E-box binding zinc finger transcription factor induced in TGF-β mediated EMT (22). SIP 1and SNAIL have overlapping binding sites on E-cadherin gene with significant co-expression patterns in E-cadherin negative carcinomas (23). The expression of SIP 1 is strongly associated with carcinomas where E-cadherin promoter is hypermethylated suggesting possible repressive impact of SIP 1 on the transcription of E-cadherin (24). Another proximal activator of transcription, CArg box binding factor-A (CBF-A) and KRAB associated protein 1(KAP-1) have been identified which form a complex with calcium-binding fibroblast specific protein 1(FSP1) (25). FSP1 is an intermediate in TGF-β and EGF signaling pathways (26,27). CBF-A induces EMT by increasing the levels of N-cadherin, SNAIL and TWIST and by decreasing the levels of E-cadherin (25).
Many of the head and neck squamous cell carcinomas, which represent the sixth most frequently incident cancer in the world, have elevated expression of Nijmegen Breakage Syndrome 1 protein (NBS1) (28). NBS1 is a double strand DNA repair protein which is activated by c-myc oncoprotein (29). Up regulation of NBS1 expression activates PI3K and represses E-cadherin by activating the transcription of E-cadherin repressor, SNAIL. PI3K activation by NBS1 consequently induces anoikis resistance by inactivating BCL2-associated agonist of cell death (BAD) and decreasing BIM, also known as BCL2L11, to trigger cell proliferation through MAPK pathway (29).
Emmprin or CD 147 is an immunoglobulin family glycoprotein enriched on the surface of many cancers like breast cancer, lymphoma, oral squamous cell carcinomas, gliomas, melanoma, lung, bladder and kidney carcinomas (30). Emmprin is a potent matrix metalloproteinase inducer. Emmprin expression is directly related to high mitotic index, increase in tumor size, higher tumor grade, and poor prognosis (31). MDA-MB-436 human breast cancer cells transfected with emmprin displayed greater survival upon suspension as simulated by cultures in poly-HEMA coated wells (32). Inhibition of emmprin enhanced anoikis in suspended transfectants compared to controls. Normally, emmprin phosphorylates and degrades pro-apoptotic BIM by activating ERK1/2 which leads to anoikis resistance. The emmprin inhibition induced regain of anoikis sensitivity was mediated by decreased phosphorylation of ERK1/2 (32).
Cell adhesion molecules like integrins, cadherins, selectins, and IgCAM family of receptors function as sensors and stabilizers of normal cell-matrix and cell-cell contacts by both homotypic and heterotypic interactions (33–36). Signal transduction from these molecules through cytoplasmic adhesion complexes branches into different cellular pathways to influence the strength of net survival or net apoptotic signaling output in response to respective normal and inappropriate cell matrix contacts.
Every cell has integrins specific to its ligand in the extra cellular matrix. The integrin family of receptors in vertebrates is comprised of 18 α and 8 β subunits which upon ligation give rise to 24 different types of integrins (37). Signaling through integrins arises from the cytoplasmic domains of both α and β subunits and is further directed according to the levels and functional state of adaptor and activator molecules in cell adhesion complexes. The signals transduce from integrins to the integrin linked kinase (ILK). Phosphorylation of focal adhesion kinase (FAK) at Y925 creates a binding site for the SH2 domain of growth factor receptor-bound protein 2 (GRB2) (38). The RAS exchange factor SOS binds to GRB2 and further activates the MAP kinase pathway (39). Alpha integrins along with caveolin bind the SRC family kinase FYN through their cytoplasmic tail. The adaptor protein SHC binds to FYN and gets phosphorylated on its tyrosine residue. The GRB2-SOS complex binds to activated SHC and triggers downstream signaling through MAPK pathway (40, 41).
Normally, integrins increase the BCL2/BAX ratio to induce cell survival input in normal extracellular matrix environment and elevated expression of specific integrins induces chemo-resistance (42). Activation of MAPK pathway in adherent conditions by integrins and growth factor mediated signaling through focal adhesion kinase (FAK) leads to increased p-ERK2 (43). Phosphorylated ERK2 in turn phosphorylates BIM leading to ubiquitination and degradation of pro-apoptotic BIM (44). Experimental studies have revealed that normally cell detachment up regulates the pro apoptotic protein BIM in securing it as a cell death trigger in anoikis (45). The interaction of BIM with BCL-xL prevents the dimerization of BCL-2 and BCL-xL, which otherwise normally dimerize to block the function of cytochrome c release regulating BAX proteins in mitochondria (46). Hence, up regulation or changes in the type of either α or β subunits of integrins influence the downstream signaling cascades to enhance or suppress cell survival in a cell and extra cellular matrix ligand specific manner. Many cancer cells sequentially up regulate and switch the integrins during initial phase of oncogenic transformation and later while invading and metastasizing to other organs.
Normal epithelial cells express the collagen receptor α2β1 and laminin receptors α3β1 and α6β1 (47,48). Hyper proliferating epithelial cells over express αvβ5 and αvβ6 integrins (49,50) while the anoikis resistant squamous carcinoma cells (SCC) over express αvβ6 relative to αvβ5 (51,52). To test the impact of specific pattern of changes in these integrins, αv lacking H357 human SCC cells were transfected with αv integrin which associated with β5 as αvβ5, leading to proliferation without differentiation (53). Cells expressing αvβ5 were sensitive to anoikis and did not activate AKT. Inhibition of caspases by z-VAD fmk significantly rescued anoikis induced death in these cells. Later, expression of β6 integrin in these cells lead to increased and preferential association of αv with β6 instead of endogenous β5 subunit to form αvβ6 which increased invasiveness of cells. Interestingly αvβ6, contrary to αvβ5, stimulated AKT and induced anoikis resistance and invasiveness in H357 cells (53). In another case of integrin switch, melanoma cells masked the sensing of integrin-ligand mismatch during dermal invasion and acquired anoikis resistance by increasing the expression of αvβ3integrin, which is compatible with dermal collagen. Inhibition of αvβ3 in these melanoma cells by antibodies induced anoikis upon suspension (54). These are classical examples of an ideal sequence where tumors selectively switch integrin subunits for initial local proliferation without differentiation, characteristic of carcinoma in situ, and later express higher affinity subunits which collectively enhance invasiveness and anoikis resistance.
Talin is an activator and adaptor protein which forms a complex with various other signaling molecules like the cytoplasmic tail of β integrins, vinculin, FAK, SRC kinases, paxillin and p130 CAS (55). The association of talin with the β integrin subunit cytoplasmic tail is essential for the acquisition of ligand receptive active conformation in the extracellular integrin complex and this makes the talin and β integrin association vital in regulating the integrin mediated adhesion and signal transduction. Molecular structure of talin reveals a large C terminal rod domain and an N terminal FERM domain constituted by three sub domains F1, F2 and F3 (56,57). Talin interacts with both membrane distal (MD) domain and helix forming membrane proximal (MP) domains of β3 integrin tail. Talin is located on chromosome 9p which is deleted in many of the primary prostate cancers (58,59). Differential gene expression studies in normal muscle and rhabdomyosarcoma cells has revealed decreased expression of talin mRNA in rhabdomyosarcoma which may contribute to disregulated integrin signaling (60).
The expression of FAK is increased in the pancreatic carcinoma cells proportional to the malignant potential of cells (61). FAK is a tyrosine kinase comprised of an NH2 terminal FERM domain, a central kinase domain, two proline rich motifs and a focal adhesion domain in the COOH terminal. Normally, the FERM domain directly interacts with the kinase domain and inhibits the activation of FAK. This inhibition is released upon targeting of FAK to the focal adhesions where FERM binds to the cytoplasmic integrin domains and unmasks the kinase domain (62). The phosphorylation of Y397 in the linker region between FERM and kinase domains is a rate limiting signaling step which is achieved by integrin linked kinase (ILK) and trans auto-phosphorylation of FAK (63). SH2 domains of SRC family kinases bind to the phosphorylated Y397 on FAK whereas GRB2 binds to the FAK at phosphorylated Y925 and activates MAPK pathway and decreases pro-apoptotic BIM levels in FAK over expressing cells. FAK at the hemidesmosomes also signals through PKB/AKT pathway to phosphorylate and sequester anti-apoptotic BAD with 14-3-3 protein leading to anoikis resistance. FAK also inhibits caspases-2, 3, 8 and 9. FAK suppresses apoptosis by activating c-Jun N-terminal kinase (JNK) (64), and inhibits the interaction of receptor interacting protein (RIP) with the death receptor complex (65). Silencing of FAK by siRNA increases caspase activation and enhances anoikis in anoikis resistant MiaAR cell lines developed from anoikis sensitive MiaPaCa2 cell lines (61). Tumor associated carbohydrate antigens like GD2 glycolipids are over expressed in small cell lung cancer (SCLC) and mediate anoikis resistance by reinforcing FAK to cell adhesion complexes at tight junctions (66). Inhibiting GD2 mediated FAK signals or siRNA mediated silencing of FAK in GD2 positive cells leads to restoration of anoikis sensitivity in SCLC (67).
The non receptor kinase SRC forms a complex with FAK in focal adhesions and regulates the adhesion mediated cell signals. SRC is over expressed in 80% of human colon cancers (68,69). The expression of SRC is strongly associated with progressive staging and poor clinical prognosis (70,71). Higher tumor staging points to the possibility of greater anoikis resistance as staging, being a measure of tumor spread or extent of metastasis reflects the ability of tumor cells to survive matrix detachment as well as the refractoriness of tumor to cell death induced by attachment to inappropriate extra cellular matrix. SW480 colon carcinoma cell lines with low SRC activity are more sensitive to anoikis than SRC over expressing HT29 cells. Anoikis sensitivity induced in SW480 cells due to low SRC levels in spite of concomitant presence of activated oncoprotein K-RAS conveys the greater dependence of these cells on survival and anti apoptotic signals relayed by SRC relative to RAS survival signals. Amplified RAS signaling could not rescue the incidence of anoikis induced death in cells with low SRC levels (72). Over-expressing SRC in SRC-deficient SW480 cells induced anoikis resistance and inhibiting SRC in SRC over-expressing HT29 human colon cancer cells using SRC inhibitor PD173955 restored anoikis sensitivity (72). v-SRC phosphorylates AKT on Y315 and Y326 and activates it, which enhances further downstream AKT mediated BAD inactivation to eventually confer anoikis resistance phenotype (73).
Cells transformed by Rous sarcoma virus (RSV) contain high levels of phosphorylated paxillin (74). Paxillin is a 68 kDa protein, which is phosphorylated and activated at Y118 by other proteins like FAK in cell adhesion complexes. Phosphorylated paxillin serves as a binding site for SH2 domain containing oncoproteins like v-CRK (75). p130-CAS is a multi-functional adaptor protein present in cytoplasmic integrin-actin cytoskeletal adhesion complexes. Its cleavage due to caspases and calpain triggers anoikis upon cell suspension (76). p130-CAS binds to the FAK and undergoes phosphorylation creating a binding site for CRKII-C3G, a Rap1 GTPase which can attenuate proliferative and survival signal of RAS. CRKII-C3G can independently activate B-RAF and hence MAPK pathway. Cell matrix detachment leads to dephosphorylation and cleavage of p130-CAS in anoikis sensitive normal epithelial cells where phosphorylation of p130-CAS is adhesion dependent (77). Anoikis resistant tumors like lung adenocarcinoma cells have constitutively phosphorylated p130-CAS which resists its cleavage to simulate signaling cascades of adhesion status even upon suspension (77).
Adaptor protein vinculin is involved in forming and reinforcing signaling complexes formed by both cadherins and integrins. Vinculin exists in an inactive conformation with its head (Vh) and tail (Vt) domains. These are exposed by interactions with either vinculin binding site (VBS3) of talin or α-catenin (78,79). Vh-VBS3 talin binding leads to conformational changes in the α helices of Vh, which displace Vt, giving vinculin an active conformation to bind to α actinin and stabilize intracellular cell adhesion complexes (80). Vinculin null cells have shown reduced susceptibility to cell matrix detachment (81) and consequent high motility and invasion (82). PTEN is a tumor suppressor protein which de-phosphorylates and inactivates FAK, SHC and PIP3 in the cell membrane (83). PTEN is frequently mutated in gliomas and its expression correlates positively with anoikis resistance. Restoration of PTEN expression increases detachment induced cell death in gliomas (84).
The integrin-talin-paxillin-actin complex at the hemidesmoses is a vital signaling node, which senses extracellular matrix and transduces the signals through various proteins like FAK and paxillin to downstream signaling cascades (85). Many proapoptotic proteins like BIM and BMF co-localize with cytoskeleton which underscores the importance of integrity of cytoskeleton in turning on the switch to anoikis (86). Cellular cytoskeleton is prone for disruption in suspended cells due to lack of ECM ligand mediated stabilization of integrin-talin-paxillin-actin complexes (87,88). Pro-apoptotic protein BIM localizes to dyenin light chain-1 (DLC1) in microtubules (89). Disruption of microtubules by taxol has shown to release BIM which co-localizes with BCL-xL. This inhibits apoptosis inhibitory BCL2-BCL-xL heterodimer formation and triggers cytochrome c release to activate anoikis (89). BMF localizes to DLC-2 in actin/myosin filaments and binds to anti-apoptotic BCL2 upon release from cytoskeleton in matrix deprived conditions to initiate an anoikis response (90).
Cadherins are glycoproteins with single span trans membrane domain and constitute the cell-cell adhesion receptor complexes by forming homophilic interaction between their histidine-alanine-valine (HAV) domains and the region between tryptophan residues and hydrophobic pockets in the most amino-terminal cadherin domains in a calcium dependent manner (91). E-cadherin is a type I cadherin which forms homophilic interactions between the immunoglobulin domain in its extracellular region and the respective domain of another E-cadherin molecule on contacting cells in a calcium dependent manner. It regulates the α and β catenin pools in the cytoplasm by sequestering these molecules at its intra cytoplasmic cadherin-catenin-actin complex in adherens junctions (92). Promoter hyper-methylation, transcriptional repression and occasional gene mutations in the E-cadherin gene lead to the loss of expression of E-cadherin or over expression of non-functional protein which trigger the oncogenic transformation of benign epithelial cells consequent to signals transducing from aberrant and enhanced cell adhesion signals (93,94).
Loss of E-cadherin in gastric cancers leads to decreased cell-cell contacts and release of β-catenin from cytoplasmic adhesion complex followed by its translocation to the nucleus where it activates the tumor promoting genes (95). E-cadherin mediated contacts are also disrupted by enzymatic cleavage by matrix metaloproteases (MMPs). The soluble 80 kDa E-cadherin produced by proteolytic cleavage of MMPs promotes further cell invasion by up regulating MMP2, MMP9 and MMP14 (96). E-cadherin in p53 deficient mice also acts as a tumor suppressor and loss of E-cadherin in these mice precipitates the incidence of invasive and metastatic tumors similar to the human invasive lobular carcinoma of breast (97).
In Ewing sarcoma cells cultured in suspended conditions there was up regulation of E-cadherin levels and activation of ERBB4, PI3K and AKT, which resisted anoikis as evident by rapid formation of multi-cellular spheroids (98). Addition of calcium chelators, antibodies to E-cadherin or induction of dominant negative form of E-cadherin increased anoikis sensitivity of suspended cells but had no impact on viability of adherent cells (98). Many cancerous epithelial cells also switch the expression of cadherins leading to decrease in E-cadherin and increase in N-cadherin. N-cadherin recruits PI3K which in turn activates AKT and induces anoikis resistance (99).
Immunoglobulin family of cell adhesion molecules (Ig-CAMs) play a vital role in maintaining the integrity of cell-cell contacts and relay the adhesion signals to the intracellular signaling cascades. Carcino embryonic antigen (CEA) is over expressed in a wide range of human malignancies including breast, lung and colon cancers. Increased CEA levels potentiate the interaction of integrin α5β1 subunit with its ligand fibronectin leading to polymerized “cocoon” fibronectin around the cells (100). This leads to increased integrin mediated survival and anti apoptotic signaling through ILK-PI3K and MAPK pathway (101). When this process is disrupted by monoclonal antibodies against fibronectin or α5β1 integrin anoikis sensitivity as well as cell differentiation is restored (100). CEAs have usually transmembrane linkage but they can also link to cell membrane through glycosyl phosphatidyl inositol (GPI) anchors. The non-synonymous mutations in the anchor determining domain of CEA lead to a shift in their linkage from TM to GPI anchorage. This transition of CEA to GPI anchorage confers anoikis resistance and favors malignant transformation of cells (102).
The CEA receptor CEACAM6 is differentially expressed in pancreatic adenocarcinoma cells and its expression is proportional to the malignant potential of the cancer cells. Over-expression of CEACAM6 in these pancreatic tumors leads to increased phosphorylation of AKT which in turn phosphorylates and sequesters the pro apoptotic protein BAD with the 14-3-3 protein (103). Silencing of CEACAM6 expression in pancreatic tumor cell lines restored anoikis sensitivity, which was further corroborated by reduction in metastasis in the mice xenografts of pancreatic adenocarcinoma (103).
Caveolin-1 is a cell membrane molecule which is increased in multi drug resistant colon cancer cell lines (104). Elevated expression of caveolin-1 is associated with drug-resistance and poor prognosis in non-small cell lung cancer (105). Caveolin-1 enhances resistance to anoikis by increasing the IGF-IR expression and by phosphorylating pp340, a substrate of PKB/AKT (106). Transfection of mammary cancer cell line, MCF-7, with caveolin-1 decreased the expression of p53 levels compared to controls which explains the resistance to anoikis mediated cell death (106). Claudin (CLDN) family of transmembrane proteins plays a vital role in establishing the architecture of tight junctions (107). Claudins are over expressed in a wide variety of human cancers and their localization and signaling potential makes them interesting targets in anoikis research and anticancer drug development (108).
Galectin-3 is a 31 kDa beta galactose family lectin, which is not normally expressed in hepatocytes but over expressed in hepatocellular carcinoma cells and associated with poor prognosis (109,110). G1/S phase arrest induced by galectin-3 resists anoikis in human breast cancer cells and it is mediated by decrease in cyclin E and cyclin A levels, increase in P21 WAF1/CIP1 and cyclin A expression. Galectin-3 also induces cyclin D1 in anchorage independence states by binding to multiple cis elements like SP1 and CREB (111). Cyclin D1 associated kinase may facilitate to surpass apoptosis sensitivity in G1 phase whereas G1/S phase arrest induces anoikis resistance by repressing BIM levels. Galectin activity can be controlled by phosphorylation at its Ser 6 residue (112,113). Ser 6 phosphorylation by casein Kinase I reduces its ability to bind ligands laminin and asialomucin whereas dephosphorylation favors normal ligand binding in ECM. Thus Ser 6 Phosphorylation of galectin-3 favors ligand disengagement as well as cell detachment and simultaneously protects the cells from anoikis by inducing G1/S phase arrest and enhancing p-ERK mediated suppression of BIM (114,115). Hence tumor specific galectin inhibition presents a very effective target in galectin over expressing tumors to limit both tumor growth and metastasis by restoring anoikis sensitivity.
The significance of anoikis in cancer therapy is self-explaining in that the major cause of death in malignancies is metastases, a consequence for which anoikis resistance is a natural molecular prerequisite. The inherent nature of anoikis to recognize wide and deep spectrum of molecular changes involved in de-adhesion, cytoskeletal integrity and cell shape makes this intrinsic cellular immunity against cancer an attractive choice to explore and rebuild as a mighty fortress against oncogenic forces induced into the cells by genetic as well as environmental factors in cancer predisposed patients. Anoikis sensitizing drugs present with a great possibility for reduction in the off target cytotoxic effects produced by conventional broad spectrum apoptotic drugs. Anoikis targeted anti-cancer therapy is of particular relevance in congenital hypertrophies and mixed cell tumors like teratomas in infants, where least cytotoxic effects of anti cancer drugs attract the gravity of making the right choice of therapy due to the need for shielding developing bone, brain and other tissues from off target cytotoxicity. In this regard, the further study of the dynamics of specific molecular spectra of anoikis in normal tissues and respective carcinomas presents a precious and deserving choice to pursue as one of the most effective and highly relevant strategies to prevent and contain the invasive and metastatic urge of immortalized cancer cells by advanced class of novel anti-cancer therapeutic drugs.
This work was supported in part by USPHS grant CA 77495 and CA 104661, Cancer Research Foundation of North Texas, and Institute for Cancer Research & the Joe & Jessie Crump Fund for Medical Education.