Prognostic Molecular Markers in Soft Tissue Sarcoma
Soft tissue sarcomas (STS) is a group of malignant tumors arising from extraskeletal connective tissues. They are rare tumors and show high mortality rates. In our study, we sought to elucidate the prognostic impact of molecular factors participating in regulating tumor cell behaviour from benign to malignant and to unravel the impact of the tissue expression of these factors on patients’ survival.
The study is based on tissue microarrays of STSs from 249 patients, from North Norway and Arkhangelsk region. Immunohistochemistry was used to evaluate marker expression.
We have investigated prognostic impacts of 15 proteins. Among them, TGF-ß, fascin, NF-?B, PKC-?, PI3K, p-Akt Thr308, Akt 2 and PGR have shown negative influence on patients’ survival, and impacts of TGF-ß and PI3K were unfavorable regardless of age, gender or other characteristics of the patient. Interesting, PGR and ER expression by STS was gender-restricted, being invariably adverse in men and neutral or even favorable in female patients. Moreover, the site of Akt phosphorylation (Thr308 and Ser473) was shown to impart diverse prognostic values in a gender-dependent fashion.
Our findings may help to identify subgroups of patients with aggressive tumors requiring adjuvant therapy which, due to relationship of many investigated proteins with female steroid hormone receptor proteins, could include specific endocrine treatment.
Molecular markers of tumor progression in soft tissue sarcomas.
Soft tissue sarcomas (STS) are malignant tumors arising from connective tissues. They are heterogeneous neoplasms, but comprise about 0,5 % of adult malignancies. Approximately 50% of the STS patients will succumb to their disease because of metastasis or local relapse.
The prognostic factors determining tumor progression include tumor grade, size, location, depth, histological entity, positive resection margins and local recurrence.
Molecular mechanisms regulating tissue changes from benign to invasive and finally to metastatic neoplasia is an area of growing scientific interest. There are many basic research studies which discovered roles of different molecular markers in cancer development and progression. However, most of them deal with cell cultures and prognostic influence of these factors on patient’s fate cannot therefore be shown. The sense of our translational research is to find out the impact of the tissue expression of these factors on patients’ survival.
To achieve this objective, tumor samples and clinical data from 249 patients, both from North Norway and Arkhangelsk region with non-GIST STS were obtained, and tissue microarrays (TMAs) were constructed. Immunohistochemistry (IHC) was used to evaluate marker expression in tumor cells.
The markers whose prognostic impacts we investigated by far were transforming growth factor-ß (TGF-ß), fascin, nuclear factor-kappa B (NF-?B) p105, protein-kinase C-zeta (PKC-?), partitioning-defective protein-6 (Par-6), E-cadherin, vimentin, phosphoinositide 3-kinase (PI3K), Akt isoforms, PTEN and receptors for estrogen (ER) and progesteron (PGR). All of them were described as tumor-promoting factors in vitro.
Among these, TGF-ß, fascin, NF-?B, PKC-?, PI3K, p-Akt Thr308, Akt 2 and PGR were shown to have negative influence on patients’ survival, and TGF-ß and PI3K were independent predictors of adverse outcome in STS patients, i.e. they were unfavorable regardless of age, gender or other characteristics of the patient. Interesting, PGR and ER expression by STS was invariably associated with poor prognosis in men, whereas there was shown no influence of PGR expression and even favourable influence of ER on survival of female patients. Moreover, we showed that both TGF-ß, p-Akt Thr308 and p-Akt Ser473 had gender-dependent impact on survival of STS patients, especially strong in coexpression with female steroid hormone receptors. Additionally, diverse prognostic values depending on the site of Akt phosphorylation were shown.
Our findings may help to identify subgroups of patients with aggressive tumors requiring adjuvant therapy which, due to relationship of both the PI3K/Akt pathway components and TGF-ß with female steroid hormone receptor proteins, could include specific endocrine treatment.
Prognostic impact of peritumoral lymphocyte infiltration in soft tissue sarcomas.
BMC Clin Pathol 2012;12():5. Epub 2012 feb 29
Prognostic impacts of hypoxic markers in soft tissue sarcoma.
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Prognostic impact of CD57, CD68, M-CSF, CSF-1R, Ki67 and TGF-beta in soft tissue sarcomas.
BMC Clin Pathol 2012;12():7. Epub 2012 mai 3
High expression of CD20+ lymphocytes in soft tissue sarcomas is a positive prognostic indicator.
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Inhibitor of neuronal nitric oxide synthase improves gas exchange in ventilator-induced lung injury after pneumonectomy.
BMC Anesthesiol 2012;12():10. Epub 2012 jun 21
Prognostic impact of Jab1, p16, p21, p62, Ki67 and Skp2 in soft tissue sarcomas.
PLoS One 2012;7(10):e47068. Epub 2012 okt 5
The prognostic impact of TGF-ß1, fascin, NF-?B and PKC-? expression in soft tissue sarcomas.
PLoS One 2011;6(3):e17507. Epub 2011 mar 3
PMID: 21390241 - Inngår i doktorgradsavhandlingen
Estrogen receptor and progesterone receptor are prognostic factors in soft tissue sarcomas.
Int J Oncol 2011 Apr;38(4):1031-40. Epub 2011 jan 24
PMID: 21271213 - Inngår i doktorgradsavhandlingen
The prognostic impact of Akt isoforms, PI3K and PTEN related to female steroid hormone receptors in soft tissue sarcomas.
J Transl Med 2011;9():200. Epub 2011 nov 22
PMID: 22107784 - Inngår i doktorgradsavhandlingen
Prognostic impact of lymphocytes in soft tissue sarcomas.
PLoS One 2011;6(1):e14611. Epub 2011 jan 27
Fibroblast growth factor 2 orchestrates angiogenic networking in non-GIST STS patients.
J Transl Med 2011;9():104. Epub 2011 jul 6
The prognostic impact of Akt isoforms, PI3K and PTEN in soft tissue sarcomas
The 16th World Congress on Advances in Oncology & 14th International Symposium on Molecular Madicine, 6-8 October, 2011, Rhodes Island, Greece
Angiogenic Markers as Prognostic Factors in Soft Tissue Sarcomas
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- Tom Dønnem
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- september 2012
- Lill-Tove Busund