Veli-Matti Kosma

Expression of Extracellular Matrix Components Versican, Chondroitin Sulfate, Tenascin, and Hyaluronan, and Their Association with Disease Outcome in Node-Negative Breast Cancer

Purpose: The purpose is to determine whether the levels of expression of extracellular matrix components in peritumoral stroma are predictive of disease outcome for women with node-negative breast cancer. Experimental Design: Tumor tissue from 86 patients with node-negative breast cancer was examined by immunohistochemical staining for the expression of versican, chondroitin sulfate (CS), tenascin, and hyaluronan (HA). With the exception of HA, the expression of the extracellular matrix components was measured by video image analysis. Statistical correlation of the immunohistochemical data with clinicopathological characteristics and disease outcome was performed. Results: All of the extracellular matrix components were present in the peritumoral stroma of the entire study cohort. In contrast, immunoreactivity within the cancer cell was observed in 82% of tumors for HA, 12% for CS, and 4% for tenascin; no immunostaining of cancer cells for versican was observed for any of the tumors. Cox regression and Kaplan-Meier analyses indicated that elevated expression of stromal versican predicted increased risk and rate of relapse in this cohort. Elevated expression of tenascin was predictive of increased risk and rate of death only. Although neither CS nor HA were predictive of disease outcome in this cohort, tumor size was predictive of increased risk and rate of both relapse and survival. Conclusions: Elevated expression within peritumoral stromal matrix of versican and tenascin was predictive of relapse-free and overall survival, respectively, in women with node-negative breast cancer.

Genetic alterations in the peritumoral stromal cells of malignant and borderline epithelial ovarian tumors as indicated by allelic imbalance on chromosome 3p.

Stromal accumulation of hyaluronan in epithelial ovarian cancers is an independent predictor of tumor spreading and unfavorable outcome of the disease. We started to screen for chromosomal causes of this accumulation by studying deletions in 3p21.3, a region harboring 3 hyaluronidase genes (HYAL1‐3) among other potentially important tumor suppressors. Using 6 microsatellite markers from this region, allelic imbalance was found in 60–87% of the informative tumor cells microdissected from histologic sections of 58 patients with epithelial ovarian cancer. However, adjacent stromal cells originally intended as controls showed allelic imbalance at a frequency almost as high as the tumor cells (52–80%). A further laser capture microdissection on 10 borderline tumors also showed a high rate of allelic imbalance, both in the epithelial and stromal cells, but with a pattern slightly different from cancers. Allelic imbalance in the tumor epithelium or stroma was not correlated with the accumulation of hyaluronan or clinicopathologic parameters, including tumor stage and grade. The results suggest that factors other than inactivation of the HYAL1‐3 genes are responsible for hyaluronan accumulation in epithelial ovarian tumors. Moreover, the results indicate that the stromal cells of the epithelial ovarian cancers not only respond to the signals from malignant epithelium but also have themselves undergone genetic alterations in markers partly identical to those in the cancer epithelial cells and may actively contribute to the development of the tumor from its early stages to the late determinants of patient mortality.

Versican in epithelial ovarian cancer: Relation to hyaluronan, clinicopathologic factors and prognosis

Versican, a proteoglycan previously reported to increase in other malignant tumours, was studied immunohistochemically in 299 primary epithelial ovarian cancers, their 43 metastases and 6 normal ovaries to evaluate its prognostic value and relation to hyaluronan, another extracellular matrix molecule increased in cancer and a binding partner of versican. The stainings were scored according to the area percentage of strong versican signal of total peri‐ and intratumoural stroma as low (<15%) or high (≥15%). Epithelial staining of the tumours was scored as positive or negative. Low and high area percentage of strong stromal versican staining were observed in 133 and 166 carcinomas, respectively. A low area percentage of strong stromal versican staining correlated with mucinous histology (p = 0.019) and early International Federation of Gynecologists and Obstetritians (FIGO) stage (p < 0.0005), whereas a high percentage was associated with reduced 5‐year survival rate of the patients (44% vs. 32%; p = 0.032). Versican was associated with the cancer cells in 151 tumours and correlated with clear cell histology (p < 0.0005), early FIGO stage (p = 0.049) and increased recurrence‐free survival (63% vs. 47%; p = 0.032). However, in Coxs multivariate analyses with the conventional prognostic factors included, neither stromal nor cancer cell‐associated versican reached a significant prognostic value. Versican is thus enriched in the malignant stroma surrounding and promoting the growth of ovarian cancer, probably acting with hyaluronan, and associates with unfavourable prognosis but does not constitute an independent indicator of patient survival.

Promotion of intestinal tumor formation by inulin is associated with an accumulation of cytosolic β‐catenin in Min mice

Inulin, polydisperse β (2‐1) fructan, has been suggested to protect against colon carcinogenesis and is currently used in a number of food applications. However, the data regarding the role of inulin in intestinal carcinogenesis remains controversial since the results of our previous study suggested that inulin promotes intestinal tumor formation in Min mice, an animal model for intestinal cancer with a mutation in the Apc tumor suppressor gene (Carcinogenesis 2000;21:1167–73). In our present study, we further examined the effects of inulin on intestinal tumor formation in Min mice by carefully analyzing β‐catenin expression and cellular localization at 3 different time points during the tumorigenic process. Min mice were fed a high‐fat inulin‐enriched (10% w/w) diet or the high‐fat diet without any added fiber from the age of 6 weeks to the ages of 9, 12 or 15 weeks. The results showed that inulin significantly increased the number (by 20%) and especially the size (by 44%) of adenomas in the small intestine. At week 15, the promotion of tumor development was accompanied by an accumulation of cytosolic β‐catenin in the adenoma tissue. In the normal appearing mucosa, levels of membrane β‐catenin and PCNA were reduced in the inulin‐fed mice, possibly indicating impaired enterocyte migration. These data do not support the earlier suggestions on the cancer preventive effects of inulin and emphasize the need for further research and evaluation where health claims for inulin are concerned.

Myometrial Inflammation in Human Delivery and Its Association With Labor and Infection

The presence of inflammation in decidual and myometrial samples as defined by histopathologic examination and the association between the myometrial inflammation and different maternal infectious morbidity and labor-related clinical variables were evaluated in 648 consecutive women who underwent cesarean section at various gestational periods. Altogether, 1,205 histologic (559 decidual and 646 myometrial) samples were studied. In normal pregnancies, myometrial inflammatory lesions were detected rarely before parturition, indicating their abnormality in these cases. After ruptured fetal membranes with advanced cervical dilatation and in patients with clinical chorioamnionitis, myometrial samples commonly were infiltrated by leukocytes, up to moderate and marked densities. Moderate to marked myometrial inflammation showed no diagnostic value in high-risk term parturients for the prediction of postoperative endometritis. Our study is the first to show the frequency of myometrial inflammation in nonselected consecutive pregnant women and, thus, is important for better understanding the myometrial inflammatory response during human parturition.

Frequent gene dosage alterations in stromal cells of epithelial ovarian carcinomas.

Stromal cells are an active and integral part of epithelial neoplasms. We have previously observed allelic imbalance on chromosome 3p21 in both stromal and epithelial cells of ovarian tumors. This study was designed to explore gene dosage alterations throughout human chromosomes from stromal and epithelial cells of epithelial ovarian carcinomas. Thirteen stromal and 24 epithelial samples, microdissected from epithelial ovarian carcinomas, were analyzed using multiplex ligation‐dependent probe amplification technique. Analysis covered 110 cancer related genes. Frequent genetic alterations were detected both in the stroma and epithelium of ovarian carcinomas. The mean number of altered genes per tumor was 10.8 in stroma and 23.6 in epithelium. In the stroma, the mean number of gains was 6.6 and of losses 4.2 and in the epithelium 13.7 and 9.9. The high number of changes associated with advanced tumor stage (p = 0.035) and death due to ovarian cancer (p = 0.032). The most frequent alteration was the deletion of the deleted in colorectal carcinoma (DCC) on chromosome 18q21.3 in 62% of samples. Loss of DCC was related to endometrioid subtype (p = 0.033). Large chromosomal aberrations were detected on the basis of alterations in adjacent genes. Most importantly, 38 genes showed similar genetic alterations (gain–gain or loss–loss) in stromal and epithelial compartments of 11 tumor pairs. Thus, frequent genetic alterations in stromal cells of epithelial ovarian carcinomas resembled those of malignant epithelial cells and may indicate a common precursor cell type. Epithelial–mesenchymal transition may generate transformed cancer cells and modify the tumor microenvironment with distinct properties.

A 6‐month dermal toxicity test with dithranol and butantrone in miniature swine

Continuous topical administration of dithranol and butantrone for 6 months caused different irritation profiles in miniature swim. In paraffin wax sticks in while petrolatum, bulantrune gave rise to much less initial irritation than dithranol. but alter 2 3 weeks the situation had equalized. In gel formulations, butantrone was initially more irritant than dithranol. The vehicles themselves induced significant irritation, Signs of skin hyperplasia (parakeratosis and acanthosis) and inflammation were frequent histopathological finding at the end of the study. but no malignant changes were found. Ditlranol and butantronc did not produce any chemical hematological or serious histological abnonmalities during list treatment, suggesting a lack of systemic toxicity. No evidence of systemic absorption was Found. This long‐term study did not predict delayed irritation of butantrone observed in about % of the psoriatic patients after treatment for 1–2 months.

Hyaluronan in Human Tumors

Publisher Summary Hyaluronan has turned out to be an active regulator of cell behavior rather than solely an inert extracellular matrix component. The high concentration of hyaluronan in many embryonic tissues correlates with their rates of cell migration and proliferation. Recent reports suggest that hyaluronan is not only a prognostic indicator, but also an active participant in the disease and a novel target of therapy. There is a large body of evidence from experimental animals and in vitro models suggesting that the production of hyaluronan by tumor cells is important for their malignant behavior. The assays on tumor biopsies do not give information about the dynamic processes that control the synthesis and catabolism of hyaluronan. Analyses of clinical patient materials show that alterations in the hyaluronan content, whether on the actual malignant cells or their surrounding stroma, are tightly associated with patient prognosis. Tumor progression is highly likely when hyaluronan is abundant on the surface or within tumor cells of gastric or colon carcinoma. There are number of ways hyaluronan can be involved in the regulation of cancer growth and spreading, as suggested by experiments on animals, and studies in vitro. However, understanding the relative importance of the various aspects of hyaluronan functions and metabolism in human cancers in vivo is still lacking and warrants more research on clinical materials.Publisher Summary Hyaluronan has turned out to be an active regulator of cell behavior rather than solely an inert extracellular matrix component. The high concentration of hyaluronan in many embryonic tissues correlates with their rates of cell migration and proliferation. Recent reports suggest that hyaluronan is not only a prognostic indicator, but also an active participant in the disease and a novel target of therapy. There is a large body of evidence from experimental animals and in vitro models suggesting that the production of hyaluronan by tumor cells is important for their malignant behavior. The assays on tumor biopsies do not give information about the dynamic processes that control the synthesis and catabolism of hyaluronan. Analyses of clinical patient materials show that alterations in the hyaluronan content, whether on the actual malignant cells or their surrounding stroma, are tightly associated with patient prognosis. Tumor progression is highly likely when hyaluronan is abundant on the surface or within tumor cells of gastric or colon carcinoma. There are number of ways hyaluronan can be involved in the regulation of cancer growth and spreading, as suggested by experiments on animals, and studies in vitro. However, understanding the relative importance of the various aspects of hyaluronan functions and metabolism in human cancers in vivo is still lacking and warrants more research on clinical materials.

Hyaluronan in Human Tumors: Importance of Stromal and Cancer Cell-Associated Hyaluronan

Publisher Summary Hyaluronan has turned out to be an active regulator of cell behavior rather than solely an inert extracellular matrix component. The high concentration of hyaluronan in many embryonic tissues correlates with their rates of cell migration and proliferation. Recent reports suggest that hyaluronan is not only a prognostic indicator, but also an active participant in the disease and a novel target of therapy. There is a large body of evidence from experimental animals and in vitro models suggesting that the production of hyaluronan by tumor cells is important for their malignant behavior. The assays on tumor biopsies do not give information about the dynamic processes that control the synthesis and catabolism of hyaluronan. Analyses of clinical patient materials show that alterations in the hyaluronan content, whether on the actual malignant cells or their surrounding stroma, are tightly associated with patient prognosis. Tumor progression is highly likely when hyaluronan is abundant on the surface or within tumor cells of gastric or colon carcinoma. There are number of ways hyaluronan can be involved in the regulation of cancer growth and spreading, as suggested by experiments on animals, and studies in vitro. However, understanding the relative importance of the various aspects of hyaluronan functions and metabolism in human cancers in vivo is still lacking and warrants more research on clinical materials.Publisher Summary Hyaluronan has turned out to be an active regulator of cell behavior rather than solely an inert extracellular matrix component. The high concentration of hyaluronan in many embryonic tissues correlates with their rates of cell migration and proliferation. Recent reports suggest that hyaluronan is not only a prognostic indicator, but also an active participant in the disease and a novel target of therapy. There is a large body of evidence from experimental animals and in vitro models suggesting that the production of hyaluronan by tumor cells is important for their malignant behavior. The assays on tumor biopsies do not give information about the dynamic processes that control the synthesis and catabolism of hyaluronan. Analyses of clinical patient materials show that alterations in the hyaluronan content, whether on the actual malignant cells or their surrounding stroma, are tightly associated with patient prognosis. Tumor progression is highly likely when hyaluronan is abundant on the surface or within tumor cells of gastric or colon carcinoma. There are number of ways hyaluronan can be involved in the regulation of cancer growth and spreading, as suggested by experiments on animals, and studies in vitro. However, understanding the relative importance of the various aspects of hyaluronan functions and metabolism in human cancers in vivo is still lacking and warrants more research on clinical materials.

CHAPTER 14 – Hyaluronan in Human Tumors: Importance of Stromal and Cancer Cell-Associated Hyaluronan

Publisher Summary Hyaluronan has turned out to be an active regulator of cell behavior rather than solely an inert extracellular matrix component. The high concentration of hyaluronan in many embryonic tissues correlates with their rates of cell migration and proliferation. Recent reports suggest that hyaluronan is not only a prognostic indicator, but also an active participant in the disease and a novel target of therapy. There is a large body of evidence from experimental animals and in vitro models suggesting that the production of hyaluronan by tumor cells is important for their malignant behavior. The assays on tumor biopsies do not give information about the dynamic processes that control the synthesis and catabolism of hyaluronan. Analyses of clinical patient materials show that alterations in the hyaluronan content, whether on the actual malignant cells or their surrounding stroma, are tightly associated with patient prognosis. Tumor progression is highly likely when hyaluronan is abundant on the surface or within tumor cells of gastric or colon carcinoma. There are number of ways hyaluronan can be involved in the regulation of cancer growth and spreading, as suggested by experiments on animals, and studies in vitro. However, understanding the relative importance of the various aspects of hyaluronan functions and metabolism in human cancers in vivo is still lacking and warrants more research on clinical materials.Publisher Summary Hyaluronan has turned out to be an active regulator of cell behavior rather than solely an inert extracellular matrix component. The high concentration of hyaluronan in many embryonic tissues correlates with their rates of cell migration and proliferation. Recent reports suggest that hyaluronan is not only a prognostic indicator, but also an active participant in the disease and a novel target of therapy. There is a large body of evidence from experimental animals and in vitro models suggesting that the production of hyaluronan by tumor cells is important for their malignant behavior. The assays on tumor biopsies do not give information about the dynamic processes that control the synthesis and catabolism of hyaluronan. Analyses of clinical patient materials show that alterations in the hyaluronan content, whether on the actual malignant cells or their surrounding stroma, are tightly associated with patient prognosis. Tumor progression is highly likely when hyaluronan is abundant on the surface or within tumor cells of gastric or colon carcinoma. There are number of ways hyaluronan can be involved in the regulation of cancer growth and spreading, as suggested by experiments on animals, and studies in vitro. However, understanding the relative importance of the various aspects of hyaluronan functions and metabolism in human cancers in vivo is still lacking and warrants more research on clinical materials.