Implications of tumor progression on clinical oncology

Using the Affymetrix array technology, we previously identified an EST strongly expressed in several metastatic cell lines. In the present study, we cloned the corresponding cDNA that encodes a new glycoprotein composed of 97 amino acids and containing a trans-membrane domain. Therefore, we named it SMAGP for Small transMembrane And Glycosylated Protein. SMAGP is strongly conserved during evolution. It is expressed by normal epithelia of various organs, the protein being notably localized to the lateral face of the plasma membrane of cohesive well-polarized epithelial cells. In addition, SMAGP contains binding domains for the protein 4.1 and the PDZ domain of MAGUK proteins. Similar protein features are observed in several cellsurface proteins involved via ternary complexes in intercellular processes leading to cytoskeleton assembly as well as intracellular signalling. Thus, SMAGP might similarly be involved in a scaffolding protein complex, and therefore participate in the epithelium organization or in subsequent functions. Immunohistochemical data obtained using human breast, colon and lung cancer samples sustain this hypothesis since they showed that, in both primary tumours and metastases, reduced expression and/or cytoplasmic redistribution of SMAGP is superimposable with low histological tumour differentiation features, namely a lack of epithelial cell polarity and disorganized tissue phenotype.

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“…chemokines activation). Finally, recruitment of vascular supply is required to form macroscopic metastases (Welch, 1997;Chambers et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

SMAGP, a new small trans-membrane glycoprotein altered in cancer

2004

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“…This invasion occurs in distinct steps that include cellular binding to the basement membrane via laminin, production of type IV collagenase and other enzymes that degrade the basement membrane, and induction of a high degree of motility by local chemoattractants including laminin itself (1,7,10,13,14,16,17,45). It is thought that cells with the malignant phenotype arise spontaneously in the original tumor as a result of mutational events associated with tumor progression (46,47). The malignant phenotype can, however, also be induced in cells transformed by certain oncogenes (e.g., the ras oncogene) (48)(49)(50) or in tumor cells treated with specific agents (e.g., 5-azacytidine) (51,52 (26).…”

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confidence: 99%

17 beta-estradiol regulates and v-Ha-ras transfection constitutively enhances MCF7 breast cancer cell interactions with basement membrane.

Albini¹,

Graf²,

Kitten³

et al. 1986

Proc. Natl. Acad. Sci. U.S.A.

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The interaction of a line of human breast carcinoma cells (MCF7) with basement membrane components, particularly laminin, was altered by exposure of the cells to estrogen as well as by transfection of the cells with the v-Ha-ras oncogene. In both cases, the cells show a greater ability to attach to a laminin substrate, to migrate to laminin, to grow in the presence of a basement membrane matrix, and to cross barriers of reconstituted basement membrane. These responses were associated with an increase in the expression of laminin receptors. It is postulated that the increase in the invasive behavior of the cells treated with estrogen or transfected with v-Ha-ras is related to the increased number of laminin receptors and their interaction with laminin. Estrogen had no discernible effect on the v-Ha-ras transfected cells. It appears that in the MCF7 cells, the malignant phenotype is under hormonal control and that this control is bypassed after v-Ha-ras transfection.Transfection of MCF7 cells with the v-Ha-ras oncogene bypasses the estrogen requirement for tumorigenicity (26).To better characterize mechanisms involved in the metastatic process, we have studied the interactions of MCF7 breast cancer cells in vitro with a reconstituted basement membrane or with laminin alone in the presence of estradiol and after v-Ha-ras transfection. The matrigel, or reconstituted basement membrane, has typical basement membrane components, but these are probably not in the proportions present in these structures in situ. We find that estrogen increases the adhesion, migration, chemoinvasion, and growth of these cells in the presence of laminin or of reconstituted basement membrane. Cells transfected with v-Ha-ras oncogene express these same activities constitutively and are unaffected by estrogen. Both estrogen and v-Ha-ras transfection confer an enhanced number of laminin receptors on these cells.

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“…Likewise, the total impact of changing tumour composition is still being determined. It is already known that the generation and maintenance of heterogeneity are both tumour cell directed and tumour cell response to external environment (Welch, 1987, 1988; Welch & Tomasovic, 1985 (Fidler & Kripke, 1980). Immune cells respond to subsets of tumour cells and eliminate immunogenic portions of the tumour mass.…”

Section: Discussionmentioning

confidence: 99%

Sensitivity of locally recurrent rat mammary tumour cell lines to syngeneic polymorphonuclear cell, macrophage and natural killer cell cytolysis

Aeed

Welch²

1988

Br J Cancer

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Summary Using a recently developed model for studying the biology of locally recurrent (LR) mammary tumours in the 13762NF rat mammary adenocarcinoma system, we examined the sensitivity to polymorphonuclear cell, macrophage and natural killer cell cytolysis. The parental MTF7(T20) cell line; the 'primary' tumours which arose following subcutaneous inoculation into the mammary fat pad, scl and sc3; and the local recurrences (following surgical excision) LRI and LRla from scl, and LR3 from sc3 were all cells generally resistant to specific PMN cytolysis. LPS-activated macrophages caused 25.1%, 38.7% and 58.8% specific cytolysis in MTF7, scl and LRI cells, respectively at E:T of 20:1 and 72h co-incubation. LRla, sc3 and LR3 lysis ranged from 0-4.4% under the same conditions. Non-activated macrophages did not lyse any of the cell lines. Locally recurrent and 'primary' tumour cell lines were also not lysed by naive NK cells (range 0.5-4.0% cytolysis). NK cells activated with bropirimine, a potent immunomodulator currently being studied in clinical trials, and/or interleukin-2 were mildly more effective at killing LR cells. Our results show that locally recurrent tumours exhibit heterogeneous sensitivities and are different from 'primary' tumour cells in sensitivities to immune cell killing, but they are not necessarily more or less sensitive. Results with bropirimine-activated or IL-2-activated NK cells emphasize that nonspecific activation is insufficient to eliminate all tumour subpopulations.Local recurrence of breast carcinoma occurs in approximately 10-40% of patients initially treated with modified or radical mastectomies, depending upon a number of parameters including: nodal involvement at the time of surgery, primary tumour size and location, histologic type, whether primary and/or adjuvant therapy was administered and level of differentiation (Donnegan et al., 1966;Fisher et al., 1977;Toonkel et al., 1983). Often regional relapse indicates a poor 5-or 10-year prognosis because systemic disease occurs shortly after diagnosis (Recht et al., 1985; KarabaliDalamaga et al., 1978;Patanaphan et al., 1984;Pearlman & Jochimsen, 1979). Also sensitivity to treatment regimens are frequently different in recurrent tumours compared to the original primary tumour.We have recently developed a model for examining factors important in the biology of mammary tumours which recurred following surgical excision of the primary 13762NF mammary adenocarcinoma tumour MTF7 . We have shown that cell lines derived from local recurrences exhibit heterogeneity in metastatic potentials , sensitivities to the commonly used chemotherapeutic agents Adriamycin and 5-fluoro-2'-deoxyuridine (FUdR) and ionizing radiation and cell surface and 2-dimensional gel protein patterns . Some of the populations were more malignant (i.e. metastatic) and some were less malignant than the primary tumour. Likewise, there was no trend towards increased resistance or sensitivity to a single therapeutic approach.Significant differences in cell surface propertie...

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Implications of tumor progression on clinical oncology

Cited by 69 publications

References 122 publications

SMAGP, a new small trans-membrane glycoprotein altered in cancer

SMAGP, a new small trans-membrane glycoprotein altered in cancer

17 beta-estradiol regulates and v-Ha-ras transfection constitutively enhances MCF7 breast cancer cell interactions with basement membrane.

Sensitivity of locally recurrent rat mammary tumour cell lines to syngeneic polymorphonuclear cell, macrophage and natural killer cell cytolysis

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