S100A10 is part of the S100 protein family being calcium binding proteins of EF-hand type. The S100 family consist of 25 distinct isoforms weighing from 9 to 13 kDa (18). Twenty-two out of 25 S100 genes are located in the 1q21 chromosome region which is prone to genomic rearrangement. This indication of an unstable region supports how S100 proteins may be a relevant focus in cancer development (18).

The intracellular function of S100A10 includes calcium homeostasis, cell cycle regulation, phosphorylation, cell growth, migration and interactions with cytoskeleton components and regulation of transcriptional factors (18).

The extracellular function of S100 proteins is comparable to a cytokine-like behaviour by binding to cell surface receptors (18). S100A10 is seen to play a critical role in angiogenesis in vivo, suggesting its role in endothelial cell function (18).

S100A10 is unique in its way of being locked in a permanently open conformation (19). The binding of Annexin A2 is accommodated in the free hydrophobic space between Helix III and IV of the S100A10 dimer (19). In the cell membrane, Annexin A2 combines with S100A10 forming a 94 kDa heterotetramer of two Annexin A2 units and two 11-kDa S100A10 proteins. The Annexin A2-S100A10 heterotetramer is a key plasminogen receptor that on the cell surface mediates the formation of plasmin. S100A10 furthermore enhance the sensitivity of Annexin A2 to calcium, interfering with the calcium level needed to conduct Annexin A2 function (20). S100A10-Annexin A2 interaction seems to play a role in the cell-to-cell adhesion of breast cancer cells and multiple types of endothelium. Interaction has been shown by investigating the protein expression of Annexin A2 and S100A10 in tissue from breast cancer patients (21).

The plasminogen/plasmin system is interaction between coagulation factors and enzymes. Plasminogen is the inactive form of plasmin found in plasma and extra cellular matrix (ECM). Plasminogen is cleaved by plasminogen activators (tPa) through the hydrolysis of the Arg561-Val562 peptide bond to yield the serine protease, plasmin (22). Plasmin is an enzyme cleaving fibrin in the ECM by direct binding or by activating other proteases (23). Altogether plasminogen/plasmin/fibrin are important regulators of proteolysis of ECM, fibrin clot degradation, macrophage migration, tissue remodelling, invasion and angiogenesis (22). An overproduction of plasmin in the tumour microenvironment enhance the degradation of ECM, hereby facilitating tumour invasion (22). Annexin A2 has independent binding sites for both tPa and plasminogen. By assembling these proteins on the cell surface, Annexin A2 accelerates the production of plasmin (22). The binding site between Annexin A2 and tPa are mechanically blocked by lipoprotein(a) and homocysteine which both are arteriothrombotic agents (2). Annexin A2-S100A10 regulates 50–90% of the plasmin generation in several types of normal cells and cancer cells (24).

The binding site of HE4 to Annexin A2 is located after the 26th amino acid at the N-terminus (5). HE4 and Annexin A2 activates the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) and focal adhesion kinase (FAK) pathways (25). The ERK/MAPK signalling pathway influences proliferation, migration and apoptosis (26). FAK is a regulator of cell signalling within the tumour microenvironment and controls cell movement, invasion and survival (27).

Angiostatin is a 38-kDa internal fragment of plasminogen that interacts through the lysine binding domain on the C-terminus of Annexin A2 on the cell surface (28). This is also the binding site for plasminogen (22). By using AS to compete with plasminogen binding, ~40% of the binding to bovine arterial endothelium cells were blocked (29).

Procathepepsin B is an enzyme hosted in lysosomes. Procathepepsin B can degrade ECM proteins such as laminin, fibronectin and collagen IV, hereby facilitating invasion of the tumours cells (30). Immunohistochemistry (IHC) showed recombinant procathepsin to interact with the Annexin A2-S100A10 heterotetramer (31). Likewise, it has been shown that procathepepsin and the Annexin A2 heterotetramer co-localize in two lines of human cancer cells, one of epithelial origin and one of mesenchymal origin. Procathepsin B can alone or in interaction with Annexin A2 activate other proteolytic proteins such as urokinase-type plasminogen activator and collagenase. These proteins also degrade ECM and facilitate invasion (30).

Multiple myeloma, breast and prostate cancer are known to metastasize to the bone marrow (32) causing distinct pain and sometimes neural complications for the patients. In vivo and in vitro studies have showed how Annexin A2 and CXCL-12 co-localize in the bone marrow. Studies using whole bone marrow cells and investigating the migration of hematopoietic stem cells (HSC) demonstrated a synergistic effect of CXCL-12 bound to Annexin A2 (33). Expression of Annexin A2 in bone marrow stromal cells (BMSC) significantly increased the binding of prostate cancer (PC) cells to BMSC (34). Furthermore, studies demonstrated how CXCL-21 expression induced the migration of PC cells towards BMSC (34). Multiple myeloma cells also express Annexin A2. It was demonstrated how this Annexin A2 expression facilitated the adhesion of osteoblasts and stromal cells in the bone marrow (35).

The N-terminus of Annexin A2 is regulated by phosphorylation. Annexin A2 and S100A10 form their heterotetramer on the cell surface in response to changes in intracellular (ICL) calcium concentration (2). This presentation on the surface can be provoked by heat induced stress of the cell. By using small interfering RNAs (siRNA), targeting S100A10, it was demonstrated that by reducing S100A10 expression, the heat stimulated translocation of Annexin A2 was markedly reduced (2). This shows how S100A10 is essential to the translocation of Annexin A2 caused by mild cellular stress (2).

Phosphorylation of Annexin A2 at residue 23 by src-like tyrosine kinases plays a role in the translocation of Annexin A2 to the cell surface (2). By using tyrosine kinase inhibitors, the heat stress induced expression of Annexin A2 on the cell surface was completely blocked demonstrating how tyrosine kinase phosphorylation of tyrosine 23 in Annexin A2 is essential to the translocation to the cell surface (2). Furthermore, protein kinase C (PKC) combined with calcium phosphorylates Annexin A2. This can be inhibited by Annexin A5 by interaction with PKC and diminishing its effect thereby reducing Annexin A2 translocation. Annexin A5 might have a therapeutic function in preventing Annexin A2s adverse function in cancer development.

Initial search in PubMed database was made February 6, 2017 (Fig. 1). The following search criteria 'the organ related cancer site' and 'Annexin A2' was used. The search was combined with a screening for literature in reference sections of relevant studies. For preliminary screening of the articles, all titles and abstracts were read. A total of 62 studies were included in the review and included studies were published from 1990–2016.

In patients with ALL, elevated levels of ANXA2 and increased amounts of phosphorylated Annexin A2 relate to resistance to glucocorticoid treatment (36). Annexin A2 is phosphorylated by Src-kinase, the reaction is facilitated by S100A10 (37). Elevated Annexin A2, S100A10 and Src-kinase activity may predict drug resistance in ALL patients (36,37). By inhibiting the Src-kinase, the ALL cells were sensitised to glucocorticoid treatment suggesting that Src-kinase inhibitors might be a supplement to treatment of glucocorticoid resistant ALL patients (36). Treatment of ALL cells with anti-Annexin A2 antibody and knockdown of S100A10 abrogate ALL adhesion to osteoblasts (37). This inhibition of ALL cell adhesion to osteoblasts indicates how Annexin A2 and S100A10 influence the binding and retention of ALL cells to the bone marrow (37). Additionally, long-term engraftment assays from mice showed reduced percentage of ALL cells in blood, spleen and bone marrow if treated with agents that disrupts the Annexin A2-S100A10 interaction (37). Furthermore, using mouse monoclonal antibodies against Annexin A2 increased the effect of treatment of ALL with dexamethasone and vincristine by disruption of the binding between ALL cells and osteoblasts (37).

Overexpression of Annexin A2 in APL cells is thought to be the mechanism behind haemorrhagic complications of APL patients (38,39). The t(15;17) translocation positive APL cells express Annexin A2 in a greater manner than other leukaemia cells (38). Annexin A2 facilitates the combining of t-Pa and plasminogen on the cell surface. APL cells with t(15;17) translocation had twice as effective t-Pa dependent plasmin generation. Annexin A2 overexpression might be the mechanism for haemorrhagic complications of APL patients (38,39). By treating APL cells with siRNA targeting Annexin A2, a decreased t-Pa mediated plasmin generation have been shown (39). Furthermore, APL cells treated with all-trans retinoic acid (ATRA) showed downregulation of Annexin A2. These findings indicate that treatment with siRNA targeting Annexin A2 or ATRA could resolve hyperfibrinolysis in APL (39,40).

Annexin A2 is expressed in MM cells in 8/8 patients (35). Annexin A2 has been shown to stimulate proliferation of MM cells and to support adhesion of MM cells to osteoblasts and stromal cells (35). Other studies, suggest that siRNA silencing of Annexin A2 can induce apoptosis in MM cell lines. Furthermore, by silencing Annexin A2 the invasive potential of MM cells were significantly diminished (74). This makes siRNA targeting Annexin A2 as a potential therapeutic focus to induce apoptosis of MM cells and interfere with the invasive potential (74).

Annexin A2 is expressed mainly in the membrane of ccRCC and the amount of Annexin A2 in ccRCC was higher compared to normal tissue (41). In primary ccRCC tumours, the expression of Annexin A2 was positively associated with a higher TNM-stage (P<0.05) (41,42), histological grade (P<0.05) (41), infiltration of the renal capsule (P<0.01) (41) and metastatic potential (P<0.01) (41,42). Furthermore, Annexin A2 overexpression was significantly correlated with shortened 5-year survival rate of ccRCC patients compared to patients with lower expression of Annexin A2 (P<0.01) (41).

Higher Annexin A2 expression is reported in urothelial carcinoma (55%, 175/315) compared to overexpression in 17.5% (11/63) of the non-tumour mucosa samples (P<0.01) (87). The expression of Annexin A2 was associated with the depth of invasion, lymph node metastasis and distant metastasis (P<0.05). Furthermore, Annexin A2 expression is a significant independent prognostic factor for survival among urothelial carcinoma patients (P=0.012) (87).

Annexin A2 is localized primarily in the membrane and faintly in the cytoplasm on PC cells (91). The expression level of Annexin A2 was significantly lower in the PC cases when compared to patients with benign prostate hyperplasia (P<0.01) (92,93). Lower Annexin A2 expression was negatively related to Gleason score 5–7, tumour stage, recurrence, lymph node metastasis and distant metastasis P<0.01 (92). Additionally, survival rate was significantly correlated to a downregulation of Annexin A2 expression (P<0.01) (92).

Annexin A2 expression seems to play a critical role in the homing and adhesion of PC cells to the bone marrow (34). Furthermore, it is demonstrated how Annexin A2 in bone marrow stromal cells could play a role in the resistance of PC cells to chemotherapy (34). Although low expression of Annexin A2 correlated to Gleason score 5–7, a strong and diffuse staining of Annexin A2 was seen in PC biopsies indicating an association between Annexin A2 and the most severe PC subtypes (91).

No expression of Annexin A2 is found in normal or hyperplastic ductal epithelial cells of the human mammarian tissue. On the contrary, protein expression of Annexin A2 is found in breast cancer and ductal carcinoma in situ (CIS) (43). Correspondingly, Annexin A2 has been shown to be upregulated in HER-2 negative and herceptin resistant breast cancer cells (44). Annexin A2s ability to stimulate the production of plasmin combined with the functional role of plasmin, indicates the possible role of Annexin A2 in angiogenesis and metastasis of breast cancer cells (43,94). Annexin A2 has been shown to maintain constitutive activation of the EGFR-pathway leading to cell proliferation, migration and viability (94). Annexin A2 downregulation by siRNA increased apoptosis and decreased cell viability and migration by inhibiting the Annexin A2 induced, constitutively active EGFR-pathway (44). Furthermore, it was shown that anti-Annexin A2 antibodies inhibited neo-angiogenesis by inducing apoptotic cell death of endothelial cells (94). This suggests that siRNA against Annexin A2 could be of therapeutic value in HER-2 negative, herceptin-resistant cancer cells.

Abnormal expression of Annexin A2 and S100A proteins has been reported to induce resistance to cisplatin-based chemotherapy among cervical cancer patients. IHC analysis showed increased Annexin A2 expression in cervical tumour stromal cells after chemotherapy treatment. In addition to this, Annexin A2 tumour expression was significantly higher in the group of tumours not responding to chemotherapy treatment, indicating that Annexin A2 upregulation may play a role in resistance to chemotherapy. Furthermore, Annexin A2 expression in stromal cells of cervical cancer patient is an independent prognostic factor for decreased progression free-survival (46,47). Annexin A2 was shown to be positively correlated with advanced cancer (47) indicating how expression of Annexin A2 relates to higher cancer stages.

Human papilloviruses (HPV) are sexually transmitted viruses that causally associate with the development of cervical cancers. The most common, HPV16, is an obligatory intracellular virus that must gain entry into host cells to survive (48). This HPV16 internalisation has been demonstrated to be partly facilitated by the Annexin A2-S100A10 heterotetramer. By inhibiting Annexin A2 in an endogenous manner or with anti-Annexin A2 antibodies, the HPV16 internalisation was significantly decreased.

Annexin A2 is expressed in both membrane and the cytoplasm of endometrial cancer cells in 95.2% of the endometrial carcinomas compared to 55.6% of the normal endometrium (P<0.05) (55). In vitro studies suggest Annexin A2 may play a role in the promotion of metastasis in that endometrial cancer. Knockdown of Annexin A2 resulted in the absence of lung and hematogenous metastasis (56), implying Annexin A2 to play a role in the development of distant metastasis among patients with endometrial cancer. For 91.7% (22/24) of endometrial carcinoma patients in stage III–IV, a high expression of Annexin A2 was found. The expression was significantly higher than for patients in stage I–II with 55% (33/60) (P<0.05). Overexpression of Annexin A2 is correlated with shorter overall survival (P<0.05) (55). Together, this suggests that Annexin A2 could be a potential therapeutic focus in order to avoid spread of endometrial tumours and to predict recurrence and overall survival.

Annexin A2 is expressed in the membrane (77%) and the cytoplasm (82.6%) of serous OC cells as well as the surrounding stromal cells (58.5%) (75). Annexin A2 seems to play a role in regulating cell proliferation of OC cell lines (76). A significant increase in Annexin A2 expression in FIGO-stage IV compared to stage II and III is reported (P=0.001 and P=0.005, respectively) (75). Annexin A2 expression is related to histological grade (P=0.002) (76). Furthermore, high expression of Annexin A2 was significantly related to presence of ascites (P<0.001) and malignant tumour cells in peritoneal fluid (P<0.001) (76). Downregulation of Annexin A2 in OC cells significantly reduced the ability of invasion and migration (P<0.05). By analysing metastasis from OC patients it was revealed that there was a high number of lung metastatic nodules in the high Annexin A2 expression group, whereas almost no lung metastasis were found in the low expression group (25). High stromal expression is significantly associated with reduced progression-free survival (PFS) (P=0.014) and reduced overall survival (OS) (75). Patients with high stromal Annexin A2 had a 1.8-fold increased risk of disease progression (P=0.0014) and a 1.6-fold increased risk of disease related death (P=0.046) (75). Combined with S100A10, Annexin A2 expression predicts adverse outcomes for OC patients. For patients with high expression of stromal Annexin A2 and cytoplasmic S100A10 the 5-year survival rate was 11.1% compared to 50% for the patients with low stromal Annexin A2 and cytoplasmic S100A10 (75).

siRNA targeting Annexin A2 significantly decreased motility (P=0.0069) and invasion (P=0.0047) in OC cell lines. In vivo studies in mice showed how treatment with Annexin A2 neutralizing antibodies significantly reduced the tumour burden (77). This makes siRNA targeting Annexin A2 and Annexin A2 neutralizing antibodies a potential therapeutic focus of OC treatment. Another study showed that RNA-nanoparticles harbouring Annexin A2 can be used to deliver doxorubicin into the OC cells. Knowledge of this mechanism may help overcome chemotherapy resistant OC and to minimize the adverse effect of chemotherapy to healthy tissue (78).

Annexin A2 is highly expressed in CRC cell lines, both on mRNA level and as protein (49). The expression of Annexin A2 is shown to induce significant changes on the microstructure of the cells (50). Upregulated Annexin A2 promotes proliferation, migration and invasion of CRC cells in vitro caused by the changes in microstructure (49). In studies investigating Annexin A2 using IHC, high expression of Annexin A2 was significantly correlated with tumour size (P=0.03), poorly differentiated tumours (P=0.01), depth of invasion (P=0.02) and TNM-stage (P=0.02) (51). Annexin A2 was shown to be an independent factor for poor prognosis in patients with CRC (51). Annexin A2 in the cell membrane is a characteristic for tumours with high invasiveness. This ability to invade tissue shows how Annexin A2 could affect lymph node metastasis (52,53). Annexin A2 has also been shown to be important for the effect of progastrins and gastrins, hereby partially mediating the effect of growth factors on colon cancer cells (95). Furthermore, Annexin A2 could be used to predict recurrence of CRC. The 5-year recurrence rate was 69.4% in the high expression group compared to 35.9% in the low expression group among patients with stage I–II disease (53). On the other hand, the serum Annexin A2 level is significantly lower in patients with CRC compared with healthy controls (P<0.001) (54). Low serum Annexin A2 levels were related to increased tumour size (P=0.003), higher TNM-stage (P=0.004), tumour invasion (P=0.005), lymph node metastasis (P=0.003) and distant metastasis (P=0.005) (54). This makes Annexin A2 levels in serum of interest to classify colon cancer patients.

Annexin A2 is downregulated on both mRNA and protein level in ESCC cells (88,89). Annexin A2 was found in 9.1% (2/22) of the ESCC samples compared to 90.9% (20/22) of the controls using qRT-PCR and western blot analysis. The expression of Annexin A2 was confirmed by IHC. Annexin A2 in ESCC cells is found mainly in the cell membrane. Low Annexin A2 expression is correlated with lymph node metastasis (P<0.05), depth of invasion (P<0.05) and poor differentiation (P<0.05) (88).

Annexin A2 is expressed in the cell membrane of normal epithelial cells of the oral cavity. Annexin A2 was expressed in 82% (87/106) of the OSCC cases (90). Annexin A2 is associated with histological grade (P=0.02). Low expression of Annexin A2 is seen in poorly differentiated tumours compared to well differentiated tumours (90). On the contrary, a higher expression of Annexin A2 correlated to tumour size (P=0.003) and tumour recurrence (P= 0.04) (90).

There are few studies investigating the expression of Annexin A2 and its relation to ESCC and OSCC. The studies reviewed have at low number of participants, 22 and 106, respectively, and it is therefore difficult to indicate a clear correlation between the expression of Annexin A2 and ESCC and OSCC.

Annexin A2 is found predominantly on the cell membrane of gastric cancer cells. Annexin A2 is found in non-tumour mucosa and in human gastric cancer cases in 19.6 and 40.1% of patients, respectively (57,58). The expression of Annexin A2 correlates with tumour size (57), histological type (57), depth of invasion (57), vessel invasion (57), lymph node metastasis, distant metastasis and TNM-stage (P<0.05) (57,58). Furthermore, for cancer stages I, II and III, the 5-year survival rate of the patients with high expression of Annexin A2 were significantly lower compared with 5-year survival for the patients with low expression (57).

Annexin A2 expression is localized to the cell membrane and cytoplasm of HCC cells (62,63). Annexin A2 expression was found in 73.8% (62/84) of the HCC tissues compared to 35.6% (21/59) of the benign liver disease (BLD) tissue (P<0.001) (64). Tumours with a high expression of Annexin A2 were larger in size compared to low expression tumours (P=0.016) (63,65). Annexin A2 expression significantly correlated with intrahepatic metastasis (P=0.02), portal vein thrombosis (P=0.003) and higher TNM-stage (P=0.024) (64,66). Survival analysis revealed how the high expression group had a poorer prognosis and a shortened 5-year survival rate (63,64). Furthermore, Annexin A2 seems to regulate actin remodelling thereby facilitating invasion and metastasis of HCC cells making high expression of Annexin A2 a marker for metastatic potential of HCC cells (67,68). By comparing serum levels of Annexin A2 from HCC patients and BLD patients, it was revealed that Annexin A2 was significantly elevated even at early stage HCC (P=0.0024 and P=0.0048, respectively) (69). Monitoring Annexin A2 expression levels in combination with alfa fetoprotein may contribute to a higher sensitivity and specificity in the clinical practice of diagnosing HCC (69). Ubiquitin associated protein 2 (UBAP2) has been shown to make a complex with Annexin A2, marking it for degradation. This makes UBAP2 a potential therapeutic focus for patients with HCC to counter the adverse effects of Annexin A2 (63).

Annexin A2 is localized in the cytoplasm of normal pancreatic epithelial cells. In late stage pancreatic intraepithelial neoplasia (PanIN) and invasive PDA, Annexin A2 is relocated to the outer luminal surface (79). The expression of Annexin A2 gives PDA tumour cells the ability to grow into the liver (79). Annexin A2 has been shown to co-localize with S100A6 on the cell membrane of PDA tumours. Annexin A2 combined with S100A6 contributes to PDA cell motility (81). Annexin A2 is also significantly associated with histopathological grading (P=0.029) (82). Annexin A2 promotes secretion of the class 3 Semaphorin Sema3D. It was demonstrated how Sema3D is enriched in metastatic tumours of PDA. Furthermore, Sema3D is expressed in primary PDA from patients with a poor prognosis and patients who died from widely metastatic disease (79). This indicates how Annexin A2, through Sema3D, promotes metastasis in human PDA and could predict a poor prognosis for PDA patients (79). Another mechanism by which Annexin A2 promotes invasion of PDA cells is mediated by Tyrosine 23 phosphorylation of Annexin A2 (80). Annexin A2 can interact with the p50 subunit of NF-κB independently of calcium. By interfering with NF-κB Annexin A2 helps to induce cellular viability of PDA (83). An in vivo study on mice showed how expression of Annexin A2 significantly correlated with a shortened survival rate (P=0.001) (80). Attributing to this, patients with high expression of Annexin A2 showed a significantly shortened PFS and OS compared to low expression patients (P=0.008 and P=0.033, respectively) (84). Treatment with anti-Annexin A2 antibodies prolonged the survival rate of mice compared with mice treated with isotype control IgG (P=0.02). Furthermore, microRNA-206 has shown the ability to reduce Annexin A2 plasmin production and thereby inhibiting PDA cell invasion (86).

Takano et al (84) examined the relevance of Annexin A2 in drug-resistant PDA and found high expression of Annexin A2 as an independent factor for recurrence in patients undergoing gemcitabine adjuvant chemotherapy. Knocking down Annexin A2 by shRNA significantly increased the cytotoxic effect of gemcitabine by the following downregulation of the NF-κB pathway (83).

These studies of anti-Annexin A2 antibodies, microRNA-206 and shRNA targeting Annexin A2 altogether indicate Annexin A2 to be of therapeutic relevance in patients with PDA (85).

The majority of human glioblastoma cases expressed Annexin A2 (59,60). Twenty-five out of 30 cases were Annexin A2 positive, with 11/30 cases strongly positive, 14/30 cases weakly positive and the remaining 5 cases negative (60). Annexin A2 expression is not detectable in normal glia cells (96). Furthermore, Annexin A2 is overexpressed in the cases with a higher grade tumour, pathological grade II–IV, compared to low grade tumours without infiltration (61). The 3-year OS rate of the Annexin A2 positive group was significantly lower than survival of the Annexin A2 negative group, 31.5 and 51.8%, respectively (59). Annexin A2 expression was shown to correlate with vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), P<0.05. Annexin A2's effect on glioblastoma cells through VEGF and PDGF may represent an important anti-angiogenesis therapeutic target in the treatment of glioma (60). A significant lower cell proliferation was shown after knockdown of Annexin A2 by using a wound closure rate (59). Knockdown of Annexin A2 reduced the invasiveness of glioma cells (59).

Annexin A2 is shown in cytoplasm and cell membranes in lung adenocarcinoma cells lines (70). Annexin A2 expression is significantly correlated with tumour diameter (P=0.003), pathological grade (P=0.014), pT status (P<0.001) and pleural invasion (71). High expression of Annexin A2 was associated with lymph node metastasis in comparison with tumours with low Annexin A2 expression (P<0.001) (72). Annexin A2 overexpression correlates to advanced clinical stage (P<0.001) and patients with high Annexin A2 expression have shorter survival compared to patients with low expression (P<0.001) (71,72).

Short hairpin plasmid mediated RNA (shRNA) interference is a way of post-translation gene silencing (70). A plasmid expressing a shRNA targeting Annexin A2 could effectively inhibit the expression of Annexin A2. This implies that the shRNA plasmid against Annexin A2 could be of therapeutic interest to decrease the proliferation and invasion capability of NSCLC cells (70).

Another study using immunoprecipitation and flow cytometry showed Annexin A2 expression and phosphorylation in cell lines with resistance properties to doxorubicin, vinca alkaloids and epipodophyllotoxins indicating a relation of Annexin A2 to prediction of multi-drug resistance (73).