An mTOR feedback loop mediates the 'flare' ('rebound') response to MET tyrosine kinase inhibition.

Targeted therapy significantly impairs tumour growth but suffers from limitations, among which the 'flare' ('rebound') effect. Among cancers driven by tyrosine kinase receptors, those relying on alterations of the MET oncogene benefit from treatment by specific inhibitors. Previously, we reported that discontinuation of MET tyrosine kinase receptor inhibition causes 'rebound' activation of the oncogene, with a post-treatment transient hyperphosphorylation phase that culminates into a dramatic increase in cancer cell proliferation. The molecular mechanisms behind the 'MET burst' after treatment cessation are unknown but critically important for patients. Here we identify a positive feedback loop mediated by the AKT/mTOR pathway leading to (a) enhanced MET translation by activating p70S6K and 4EBP1 and (b) MET hyper-phosphorylation by inactivation of the tyrosine-phosphatase PTP1B. The latter effect is due to m-TOR-driven PTP1B phosphorylation of the inhibitory residues Ser50 and Ser378. These data provide in vitro evidence for the use of mTOR inhibitors to prevent the 'flare effect' in MET targeted therapy, with potential applicative ramifications for patient clinical management.

Targeting the human epidermal growth factor receptor 2 (HER2) oncogene in colorectal cancer.

Human epidermal growth factor receptor 2 (HER2) is an oncogenic driver, and a well-established therapeutic target in breast and gastric cancers. Using functional and genomic analyses of patient-derived xenografts, we previously showed that a subset (approximately 5%) of metastatic colorectal cancer (CRC) tumors is driven by amplification or mutation of HER2. This paper reviews the role of HER2 amplification as an oncogenic driver, a prognostic and predictive biomarker, and a clinically actionable target in CRC, considering the specifics of HER2 testing in this tumor type. While the role of HER2 as a biomarker for prognosis in CRC remains uncertain, its relevance as a therapeutic target has been established. Indeed, independent studies documented substantial clinical benefit in patients treated with biomarker-driven HER2-targeted therapies, with an impact on response rates and duration of response that compared favorably with immunotherapy and other examples of precision oncology. HER2-targeted therapeutic strategies have the potential to change the treatment paradigm for a clinically relevant subgroup of metastatic CRC patients.

RET fusions in a small subset of advanced colorectal cancers at risk of being neglected.

Background: Recognition of rare molecular subgroups is a challenge for precision oncology and may lead to tissue-agnostic approval of targeted agents. Here we aimed to comprehensively characterize the clinical, pathological and molecular landscape of RET rearranged metastatic colorectal cancer (mCRC). Patients and methods: In this case series, we compared clinical, pathological and molecular characteristics of 24 RET rearranged mCRC patients with those of a control group of 291 patients with RET negative tumors. RET rearranged and RET negative mCRCs were retrieved by systematic literature review and by taking advantage of three screening sources: (i) Ignyta's phase 1/1b study on RXDX-105 (NCT01877811), (ii) cohorts screened at two Italian and one South Korean Institutions and (iii) Foundation Medicine Inc. database. Next-generation sequencing data were analyzed for RET rearranged cases. Results: RET fusions were more frequent in older patients (median age of 66 versus 60 years, P = 0.052), with ECOG PS 1-2 (90% versus 50%, P = 0.02), right-sided (55% versus 32%, P = 0.013), previously unresected primary tumors (58% versus 21%, P < 0.001), RAS and BRAF wild-type (100% versus 40%, P < 0.001) and MSI-high (48% versus 7%, P < 0.001). Notably, 11 (26%) out of 43 patients with right-sided, RAS and BRAF wild-type tumors harbored a RET rearrangement. At a median follow-up of 45.8 months, patients with RET fusion-positive tumors showed a significantly worse OS when compared with RET-negative ones (median OS 14.0 versus 38.0 months, HR: 4.59; 95% CI, 3.64-32.66; P < 0.001). In the multivariable model, RET rearrangements were still associated with shorter OS (HR: 2.97; 95% CI, 1.25-7.07; P = 0.014), while primary tumor location, RAS and BRAF mutations and MSI status were not. Conclusions: Though very rare, RET rearrangements define a new subtype of mCRC that shows poor prognosis with conventional treatments and is therefore worth of a specific management.

Lenalidomide normalizes tumor vessels in colorectal cancer improving chemotherapy activity.

BACKGROUND: Angiogenesis inhibition is a promising approach for treating metastatic colorectal cancer (mCRC). Recent evidences support the seemingly counterintuitive ability of certain antiangiogenic drugs to promote normalization of residual tumor vessels with important clinical implications. Lenalidomide is an oral drug with immune-modulatory and anti-angiogenic activity against selected hematologic malignancies but as yet little is known regarding its effectiveness for solid tumors. The aim of this study was to determine whether lenalidomide can normalize colorectal cancer neo-vessels in vivo, thus reducing tumor hypoxia and improving the benefit of chemotherapy. METHODS: We set up a tumorgraft model with NOD/SCID mice implanted with a patient-derived colorectal cancer liver metastasis. The mice were treated with oral lenalidomide (50 mg/Kg/day for 28 days), intraperitoneal 5-fluorouracil (5FU) (20 mg/Kg twice weekly for 3 weeks), combination (combo) of lenalidomide and 5FU or irrelevant vehicle. We assessed tumor vessel density (CD146), pericyte coverage (NG2; alphaSMA), in vivo perfusion capability of residual vessels (lectin distribution essay), hypoxic areas (HP2-100 Hypoxyprobe) and antitumor activity in vivo and in vitro. RESULTS: Treatment with lenalidomide reduced tumor vessel density (p = 0.0001) and enhanced mature pericyte coverage of residual vessels (p = 0.002). Perfusion capability of tumor vessels was enhanced in mice treated with lenalidomide compared to controls (p = 0.004). Accordingly, lenalidomide reduced hypoxic tumor areas (p = 0.002) and enhanced the antitumor activity of 5FU in vivo. The combo treatment delayed tumor growth (p = 0.01) and significantly reduced the Ki67 index (p = 0.0002). Lenalidomide alone did not demonstrate antitumor activity compared to untreated controls in vivo or against 4 different mCRC cell lines in vitro. CONCLUSIONS: We provide the first evidence of tumor vessel normalization and hypoxia reduction induced by lenalidomide in mCRC in vivo. This effect, seemingly counterintuitive for an antiangiogenic compound, translates into indirect antitumor activity thus enhancing the therapeutic index of chemotherapy. Our findings suggest that further research should be carried out on synergism between lenalidomide and conventional therapies for treating solid tumors that might benefit from tumor vasculature normalization.

Targeting the MET gene for the treatment of non-small-cell lung cancer.

Recently, a better understanding of the specific mechanisms of oncogene addiction has led to the development of antitumor strategies aimed at blocking these abnormalities in different malignancies, including lung cancer. These abnormalities trigger constitutive activation of tyrosine kinase receptors (RTKs) involved in fundamental cell mechanisms such as proliferation, survival, differentiation and migration, and consequently the aberrant signaling of RTKs leads to cancer growth and survival. The inhibition of aberrant RTKs and downstream signaling pathways has opened the door to the targeted therapy era. In non-small-cell lung cancer (NSCLC), molecular research has allowed the discrimination of different aberrant RTKs in lung cancer tumorigenesis and progression, and thus the identification of several targetable oncogenic drivers. Following the development of small molecules (gefitinib/erlotinib and crizotinib) able to reversibly inhibit the epidermal growth factor receptor (EGFR) and signaling pathways mediated by anaplastic lymphoma kinase (ALK), respectively, the MET signaling pathway has also been recognized as a potential target. Moreover, according to current knowledge, MET could be considered both as a secondary oncogenic mechanism and as a prognostic factor. Several therapeutic strategies for inhibiting activated hepatocyte growth factor receptor (HGFR) and the subsequent downstream signaling transduction have been improved in order to block tumor growth. This review will focus on the MET pathway and its role in resistance to EGFR TK (tyrosine kinase) inhibitors, the different strategies of its inhibition, and the potential approaches to overcoming acquired resistance.

Met signaling regulates growth, repopulating potential and basal cell-fate commitment of mammary luminal progenitors: implications for basal-like breast cancer.

Basal-like breast cancer is an aggressive subtype of mammary carcinoma. Despite expressing basal markers, typical of mammary stem cells, this tumor has been proposed to originate from luminal progenitors, which are downstream of stem cells along the mammary epithelial hierarchy. This suggests that committed luminal progenitors may reacquire basal, stem-like characteristics, but the mechanisms that regulate this transition remain unclear. Using mouse models, we found that luminal progenitors express high levels of the Met receptor for hepatocyte growth factor (HGF), as compared with the other mammary epithelial sub-populations. Constitutive activation of Met led luminal progenitors to attain stem cell properties, including enhanced clonogenic activity in vitro and de novo ability to reconstitute mammary glands in repopulation assays in vivo. Moreover, in response to Met signaling, luminal progenitors gave rise to hyperplastic ductal morphogenesis and preferentially underwent basal lineage commitment at the expense of luminal cell-fate specification. Opposite and symmetric results were produced by systemic pharmacological inhibition of Met. Hence, Met signaling targets luminal progenitors for expansion, impairs their differentiation toward the mature luminal phenotype and enables their commitment toward the basal lineage. These results emphasize a critical role for Met in promoting deregulated proliferation and basal plasticity of normal luminal progenitors in the mammary gland, a complex of events that may be required for sustaining the functional and phenotypic properties of basal-like breast tumors.

Scatter factor-dependent branching morphogenesis: structural and histological features.

Branching morphogenesis is a multi-step process that controls the formation of polarised tubules starting from hollow cysts. Its execution entails a series of rate-limiting events which include reversible disruption of cell polarity, dismantling of intercellular contacts, acquisition of a motile phenotype, stimulation of cell proliferation, and final re-establishment of cell polarity for creation of the definitive structures. Branching morphogenesis takes place physiologically during development, accounting for the establishment of organs endowed with a ramified architecture such as glands, the respiratory tract and the vasculartree. In cancer, aberrant implementation of branching morphogenesis leads to deregulated proliferation, protection from apoptosis and enhanced migratory/invasive properties, which together exacerbate the aggressive features of neoplastic cells. Under both physiological and pathological conditions, branching morphogenesis is mainly accomplished by a family of growth factors known as scatter factors. In this review, we will summarise the current knowledge on the biological and functional roles of scatter factors during branching morphogenesis, with a special emphasis on the phenotypic (structural and histological) consequences of scatter factor activity in different tissues.

Autoantibodies against a 72-kDa ductal cell membrane glycoprotein in a patient affected by Sjögren's syndrome and gastric MALT lymphoma.

Sjögren's syndrome is a chronic autoimmune disease affecting exocrine glands, resulting in xerostomia and xerophthalmia. Lymphocytic infiltration and fibrosis of exocrine glands as well as the presence of autoantibodies against organ-specific and non-organ-specific antigens are the hallmarks of the disease. We investigated whether some patients affected by Sjögren's syndrome might have autoantibodies directed against epithelial duct cell membrane proteins. We screened sera from patients affected by Sjögren's syndrome by indirect immunofluorescence on monkey salivary gland sections and FG-Met-2 cells (a pancreatic carcinoma cell line with ductal features) for the presence of antisalivary duct antibodies. Positive sera were employed in immunoprecipitation experiments on (35)S-methionine in vivo labeled and surface-biotinylated FG-Met-2 cells. The serum of a patient affected by Sjögren's syndrome and gastric mucosa-associated lymphoid tissue (MALT) lymphoma gave positive and distinct membrane immunostaining on FG-Met-2 cells. Immunoprecipitation with the patient's serum from (35)S-methionine-labeled cell extracts followed by sodium dodecyl sulfate (SDS) polyacrylamide gel electrophoresis (PAGE) and autoradiography showed the presence of autoantibodies against a 72-kDa protein. After biotin-surface labeling of FG-Met-2 cells, a band with identical electrophoretic mobility was immunoprecipitated by the serum, demonstrating that the 72-kDa band is a membrane glycoprotein. We demonstrated by three complementary approaches, i.e., immunocytochemistry, (35)S-methionine in vivo labeling, and cell surface biotinylation, the presence of autoantibodies directed against a duct cell membrane protein of 72-kDa in a patient affected by Sjögren's syndrome and gastric MALT lymphoma. Autoantibodies directed against this novel membrane autoantigen may be an additional serological marker in some cases of Sjögren's syndrome.

A signaling adapter function for alpha6beta4 integrin in the control of HGF-dependent invasive growth.

alpha6beta4 integrin and the Met receptor for HGF have been shown independently to promote invasive growth. We demonstrate here that Met selectively associates with alpha6beta4. In carcinoma cells expressing Met alone, HGF does not exert significant biological effects. Ectopic expression of alpha6beta4 restores HGF-regulated processes. Following Met activation, alpha6beta4 is tyrosine phosphorylated and combines with Shc and PI3K, generating an additional signaling platform that potentiates HGF-triggered activation of Ras- and PI3K-dependent pathways. In the presence of an alpha6beta4 mutant defective for Shc recruitment, Met cannot sustain HGF-mediated responses. Surprisingly, a truncated beta4 unable to bind laminins retains the activity of wild-type alpha6beta4. Such findings invoke an unexpected role for alpha6beta4 in cancer invasion as a functional amplifier of biochemical outputs rather than a mechanical adhesive device.

Osteopontin is an autocrine mediator of hepatocyte growth factor-induced invasive growth.

In epithelial cells, hepatocyte growth factor (HGF) activates a genetic program involving cell-cell dissociation ("scattering"), growth and invasiveness. The full program is not elicited by other growth factors like epidermal growth factor, and is aberrantly activated during cancer progression to the invasive-metastatic phenotype. To identify genes involved in the onset of invasive growth, we explored by cDNA microarrays the in vitro transcriptional response to HGF of mouse embryo liver cells. We identified osteopontin (OPN), a secreted matrix protein, as a major HGF transcriptional target. The wave of OPN induction is maximal at 6 h, in concomitance with the initiation of scattering, and is specific, because no other matrix protein among those explored by the microarray is affected. Interestingly, HGF, but not epidermal growth factor, promotes cell adhesion to OPN via the CD44 receptor. Scattering is significantly impaired by antibodies against OPN and CD44; conversely, constitutive OPN overexpression dramatically increases the motile and invasive responses to HGF, leading to disruption of the ordered morphogenetic program triggered by this ligand.

Integrin expression and IgA nephropathy: in vitro modulation by IgA with altered glycosylation and macromolecular IgA.

BACKGROUND: Signal transduction by mesangial cell (MC) integrins regulates cell growth and survival, extracellular matrix production, and organization. The aim of the study was to investigate human MC integrin modulation by differently glycosylated IgA and macromolecular IgA, which are thought to play a pathogenetic role in IgA nephropathy (IgAN). METHODS: MCs were incubated with purified human polymeric IgA, heat-aggregated IgA, IgA glycoforms generated by enzymatic hydrolysis of saccharide residues and serum fractions from IgAN patients, and controls isolated by lectin affinity and containing IgA with peculiar glycan patterns. Integrins were quantitated by flow cytometry. RESULTS: Cultured MCs highly expressed alphavbeta3 and some alpha3beta1; alphavbeta3 was up-regulated by matrix components (P < 0.02). In vitro desialylated and degalactosylated polymeric human IgA enhanced alphavbeta3 expression on cultured MCs (P < 0.001). Serum IgA glycoforms isolated from IgAN patients with high exposure of internal sugars, GalNAc, Neu5Ac2,6GalNAc, and Man enhanced alphav expression on cultured MCs more than healthy controls. CONCLUSIONS.: These data support the hypothesis that IgA glycation plays a role in modulating the cell-matrix interaction, and that this mechanism can be operating in IgAN.

HGF/scatter factor selectively promotes cell invasion by increasing integrin avidity.

Hepatocyte growth factor/scatter factor (HGF/SF) controls a genetic program known as 'invasive growth', which involves as critical steps cell adhesion, migration, and trespassing of basement membranes. We show here that in MDA-MB-231 carcinoma cells, these steps are elicited by HGF/SF but not by epidermal growth factor (EGF). Neither factor substantially alters the production or activity of extracellular matrix proteases. HGF/SF, but not EGF, selectively promotes cell adhesion on laminins 1 and 5, fibronectin, and vitronectin through a PI3-K-dependent mechanism. Increased adhesion is followed by enhanced invasiveness through isolated matrix proteins as well as through reconstituted basement membranes. Inhibition assays using function-blocking antibodies show that this phenomenon is mediated by multiple integrins including beta1, beta3, beta4, and beta5. HGF/SF triggers clustering of all these integrins at actin-rich adhesive sites and lamellipodia but does not quantitatively modify their membrane expression. These data suggest that HGF/SF promotes cell adhesion and invasiveness by increasing the avidity of integrins for their specific ligands.

Interactions between scatter factors and their receptors: hints for therapeutic applications.

The scatter factors, which include hepatocyte growth factor and macrophage stimulating protein, stand out from other cytokines because of their uncommon biological properties. In addition to promoting cell growth and protection from apoptosis, they are involved in the control of cell dissociation, migration into extracellular matrices, and a unique process of differentiation called 'branching morphogenesis'. Through the concerted regulation of these complex phenomena, scatter factors promote development, regeneration, and reconstruction of normal organ architecture. In transformed epithelia, scatter factors can mediate tumor invasive growth, a harmful feature of neoplastic progression in which cancer cells invade surrounding tissues, penetrate across the vascular walls, and eventually disseminate throughout the body, giving rise to systemic metastases. A much-debated issue in basic biology, which has strong implications for experimental medicine, is how to dissociate the favorable effects of growth factors from their adverse ones. Accordingly, to find agonists or antagonists with potential therapeutic applications is a crucial undertaking for current research. Domain-mapping analyses of growth factor molecules can help to isolate specific structural requirements for the induction of selective biological effects. Based on the observation that certain growth factors must undergo posttranslational modifications to exert a full response, it is possible to interfere with their activation mechanisms to modulate their functions. Finally, the identification of cell type-specific coreceptors able to potentiate their activity allows drawing of a functional body map, where some organs or tissues may be more responsive than others to growth factors. This review is focused on how, and to what extent, scatter factors can behave 'well' or 'badly' according to their molecular structure, the way they are activated, and the way they interact with cell surface receptors and coreceptors.

Growth factor-dependent activation of alphavbeta3 integrin in normal epithelial cells: implications for tumor invasion.

Integrin activation is a multifaceted phenomenon leading to increased affinity and avidity for matrix ligands. To investigate whether cytokines produced during stromal infiltration of carcinoma cells activate nonfunctional epithelial integrins, a cellular system of human thyroid clones derived from normal glands (HTU-5) and papillary carcinomas (HTU-34) was employed. In HTU-5 cells, alphavbeta3 integrin was diffused all over the membrane, disconnected from the cytoskeleton, and unable to mediate adhesion. Conversely, in HTU-34 cells, alphavbeta3 was clustered at focal contacts (FCs) and mediated firm attachment and spreading. alphavbeta3 recruitment at FCs and ligand-binding activity, essentially identical to those of HTU-34, occurred in HTU-5 cells upon treatment with hepatocyte growth factor/scatter factor (HGF/SF). The HTU-34 clone secreted HGF/SF and its receptor was constitutively tyrosine phosphorylated suggesting an autocrine loop responsible for alphavbeta3 activated state. Antibody-mediated inhibition of HGF/SF function in HTU-34 cells disrupted alphavbeta3 enrichment at FCs and impaired adhesion. Accordingly, activation of alphavbeta3 in normal cells was produced by HTU-34 conditioned medium on the basis of its content of HGF/SF. These results provide the first example of a growth factor-driven integrin activation mechanism in normal epithelial cells and uncover the importance of cytokine-based autocrine loops for the physiological control of integrin activation.

Altered expression of alpha 6 integrin subunit in oral squamous cell carcinoma and oral potentially malignant lesions.

The expression and distribution of integrin chains alpha 2, alpha 3, alpha 5, alpha 6, beta 1, beta 4, collagen type IV, laminin 1 and laminin 5 in oral squamous cell carcinoma (SCC) and oral keratoses with and without dysplasia (OL) have been studied by immunochemistry and western blotting. Focal interruptions of basement membrane protein staining were detected in SCC indicating a loss of continuity, whereas tumour nests were apparently completely surrounded by laminin 1, type IV collagen and laminin 5; the loss of basement membrane components in OL was found in only one specimen showing severe dysplasia. The localisation of integrins showed altered suprabasal and pericellular expression of the alpha 6 chain in all but one SCC, as well as in many OL samples, whereas the beta 4 subunit showed only a faint pericellular redistribution in SCC. In OL, beta 4 was often seen in a normal basally polarised distribution. Western blotting analysis confirmed that alpha 6 protein levels were abnormally high in cancerous lesions, whereas quantitative recovery of the beta 4 subunit in SCC was only minimal, suggesting a dissociation in the synthetic ratios of the two chains of the alpha 6 beta 4 heterodimer in SCC. Because alterations in the polarised expression of integrin alpha 6 beta 4 have been seen during epithelial tumour progression and wound healing, we suggest that the lack of restricted basal polarisation of alpha 6 could be an early but non-specific marker of oral malignancy, indicating that the generation of abnormal signals from the extracellular matrix may be involved.

Topography and biological role of integrins in human skin.

We report the topography of integrins in the human epidermis and in cultured human keratinocytes. Both in situ and in vitro beta 1 integrins are exposed at the cell-cell adhesion interface while beta 4 is located on the basal membrane in contact with the basal lamina. Such defined sorting identifies discrete cell membrane domains that may be involved in defining, building up, and maintaining epithelial cell polarity. The distribution of integrins is deeply altered in hyperproliferative states like those occurring in several experimental conditions and in epidermal diseases.

[Adhesion molecules in squamous cell carcinoma of the larynx: possible indication of prognosis]. / Le molecole di adesione nel carcinoma squamoso della laringe. Possibile significato prognostico.

Thirty patients with laryngeal tumors were divided into two groups on the basis of whether clinical and pathological features indicated good or bad prognosis. Samples of each tumor group were selected and examined by immunohistochemistry using mAbs, raised against integrin chains (beta 1, beta 4, alpha 2, alpha 3, alpha 6) and their ligands laminin 1 and 5, collagen type IV, two fibronectin isoforms (ED-A and ED-B) and two isoforms of tenascin known to be associated with neoplasm. Controls were provided by samples of tumor-free laryngeal mucosa removed during the surgical procedure. The normal topographical integrin pattern and the continuity of the basement membrane components was altered in both groups but the extent of these changes was significantly greater in those tumors with poor prognosis. Therefore, the groups could easily and reliably be distinguished by simply observing their immunohistochemical features. It is suggested that performing immunohistochemical analysis on biopsies may aid in early diagnosis as well as in adopting the proper therapeutic strategy to follow for these tumors. The above molecules may become one of the diagnostic tools available for head and neck surgical pathologists.

Tubulointerstitial responses in the progression of glomerular diseases: albuminuria modulates alpha v beta 5 integrin.

Proteinuria represents one of the most unfavorable prognostic factors in the progression of nephropathies. Several lines of evidence support a role for proteinuria per se in the development of interstitial fibrosis, albeit the molecular mechanisms are still unknown. We investigated the potential role of integrins expressed on tubular cells in regulating the synthesis and organization of interstitial matrix or as mediators of tubulointerstitial damage in conditions mimicking the nephrotic milieu. Under basal conditions, cultured tubular cells highly expressed alpha 3 beta 1 and, at focal contacts, alpha v beta 3. In contrast, alpha v beta 5 was weakly and diffusely distributed all over the plasma membrane. Cultures on a variety of matrix substrates (fibronectin, laminin, collagen types I and IV, vitronectin, von Willebrand factor, fibrinogen) did not induce any phenotypic change in integrin expression by tubular cells. Conversely, the addition of albumin resulted in a highly increased membrane expression of beta 5, which was organized in typical focal contacts and was related to the dose of albumin added. Immunofluorescence, flow cytometry, immunoprecipitation and RT-PCR experiments argue for a complex mechanism that includes increased post-transcriptionally regulated protein synthesis, accelerated conversion of precursors to mature forms, and increased surface delivery to discrete adhesive structures. Up-regulation of the beta 5 chain in tubular cells was confirmed in 9 out of 11 kidney biopsies from proteinuric glomerulonephritides including membranous and focal sclerosing glomerulonephritis, while it was not expressed in nonproteinuric kidneys including five biopsy specimens. This is the first report indicating that proteinuria up-regulates the surface expression and distribution of a specific integrin chain on tubular cells. These observations suggest the participation of integrins in a hitherto unexplored mechanism of tubulo-interstitial responses to glomerular injury.

Differential integrin expression in thyroid and laryngeal carcinomas.

Several laryngeal and thyroid carcinomas were studied immunohistochemically to evaluate whether the expression and distribution of integrins and basal lamina components can represent reproducible markers for correct early diagnosis and prognosis. In laryngeal cancers, the depolarization and pericellular redistribution of alpha 3 beta 1 and alpha 6 beta 4, and focal or massive fragmentation of the basal lamina, according to tumor prognosis, occurred. In thyroid carcinomas, loss of polar topography of alpha 3 beta 1 and neo-expression of alpha 6 beta 4 in histopathologically or clinically aggressive cancers were observed. Therefore, the addition of a panel of adhesion molecules to the toolbox of surgical pathologists may improve diagnostic and prognostic procedures.