Biomedical subjects

A Oikarinen

Publications and source records attributed to A Oikarinen.

At least 73 records · Page 4Linked to original sources

PubMed1995

Synthesis and degradation of connective tissue macromolecules in pachydermoperiostosis (PDP): evidence for altered processing of plasminogen activator inhibitor-1 (PAI-1).

Pachydermoperiostosis (PDP) is a hereditary disease with hyperostosis, clubbing of fingers, coarse skin and thickening of bones. Previous studies have disclosed some abnormality in the connective tissue in these patients. The purpose of the present study was to investigate connective tissue pathology in one family with PDP using fibroblast cultures. Fibroblastic cells were established from both the affected and healthy looking skin of 2 patients with PDP, and the expression of types I and III collagen, 92 kDa and 72 kDa gelatinases, metalloproteinase inhibitor (TIMP-1), human retinoic acid receptor and transforming growth factor beta (TGF beta) was analyzed. The modulation of glycoprotein synthesis, and of plasminogen activators and their inhibitors by TGF beta in vitro were also studied. The results indicated that collagen genes and gelatinases were similarly expressed in PDP and control cells, as well as the human retinoic acid receptor. TGF beta stimulated, both in PDP cells and normal cells, the synthesis of fibronectin, procollagen and plasminogen activator inhibitor-l (PAI-1), but qualitative differences could not be found. Proteolytically processed forms of PAI-1 were detected in PDP cell lines.

Adult↗

PubMed1995

Comparison of the effect of hydrocortisone, hydrocortisone-17-butyrate and betamethasone on collagen synthesis in human skin in vivo.

It has been shown previously that topical corticosteroid treatment decreases collagen synthesis in human skin in vivo and that the adverse effects are due to reduced collagen synthesis. The aim of the present study was to evaluate the effect of hydrocortisone, hydrocortisone-17-butyrate and betamethasone on collagen synthesis in human skin in vivo. Fourteen healthy male volunteers applied hydrocortisone, hydrocortisone-17-butyrate, betamethasone and vehicle twice a day for one week to four separate areas marked on their abdominal skin. The collagen synthesis rate in the skin was measured by assaying collagen propeptides from the suction blisters induced on the treated areas. Aminoterminal propeptide of type I procollagen (PINP) and aminoterminal propeptide of type III procollagen (PIIINP) were measured from skin blister fluid using radioimmunoassays. Skin thickness was measured with ultrasound. Hydrocortisone decreased the two propeptides studied in the suction blister fluids less than did hydrocortisone-17-butyrate and betamethasone, but the interindividual variation was great. Hydrocortisone-17-butyrate and betamethasone had almost similar decreasing effects on the propeptides in the suction blister fluid. Hydrocortisone decreased the concentrations of PINP and PIIINP by about 35%. In some subjects (4/14) the decline of the collagen propeptide levels was over 50%. The decline in the concentration of PINP was 63% by hydrocortisone-17-butyrate and 69% by betamethasone, while the decrease in PIIINP was 55% by hydrocortisone-17-butyrate and 62% by betamethasone. None of the treatments had any effect on skin thickness within one week. In conclusion, it seems that hydrocortisone is less atrophogenic than hydrocortisone-17-butyrate and betamethasone, as shown by radioimmunoassays for collagen propeptides. The order of inhibitory potency of the three glucocorticoids on collagen synthesis was hydrocortisone < hydrocortisone-17-butyrate < betamethasone. Thus, assay of collagen propeptides from suction blisters can be used to screen various steroids with respect to their action on collagen synthesis.

Administration, Topical↗

PubMed1995

Methotrexate-linked ventricular arrhythmias.

A 36-year-old male, who 1 year previously had survived a large anterior myocardial infarction, followed by cardiac arrest, was treated a few months for psoriasis with oral methotrexate, at single weekly oral doses of up to 10 mg, when he had to be hospitalized due to anginal pain and palpitation. Repeated 24-hour electrocardiogram recordings revealed ventricular ectopy up to 580 premature beats per hour. The ventricular premature beats were almost completely abolished after a few days' discontinuation of methotrexate therapy but recurred a few hours after an attempt to restart it had been made. A coronary angiogram showed only minimal wall abnormalities. Electrophysiological testing and endomyocardial biopsy were normal.

Administration, Oral↗

PubMed1995

Systemic oral isotretinoin therapy and flow rate, pH, and matrix metalloproteinase-9 activity of stimulated saliva.

Systemic retinoids are known to cause dryness of the mouth and changes in oral and lip mucosa. The purpose of this study was to evaluate changes in salivary variables during treatment with oral isotretinoin in patients receiving the drug for 3 months for cutaneous acne. Patients were examined 1 month after initiation of medication and approximately 3.7 months after its discontinuation. Salivary flow and pH could be measured in 8 and the relative amount of matrix metalloproteinase-9 (MMP-9) of stimulated saliva in 17 patients. The mean flow rate of stimulated saliva was lower during medication than at control examination (P = 0.0277), but no change in the mean pH value was observed during medication. The mean activity of MMP-9 during medication was higher than at control examination (P = 0.0442). The enzyme activity increased in 13 of 17 and decreased in 4 of 17 cases.

Acne Vulgaris↗

PubMed1995

Neurofibromin: expression by normal human keratinocytes in vivo and in vitro and in epidermal malignancies.

BACKGROUND: Neurofibromin is the product of the NF1 gene, the mutations of which have been linked with type 1 neurofibromatosis. The expression of neurofibromin in human skin has not been analyzed in detail. EXPERIMENTAL DESIGN: Polyclonal Ab were raised against synthetic peptides corresponding to three different sites of neurofibromin. One of the Ab selectively recognized type II neurofibromin. The localization of neurofibromin was first studied in normal human skin. Further studies concentrated on neurofibromin expression in basal cell and squamous cell carcinomas. Reverse transcription-PCR (RT-PCR) and molecular hybridizations and immunocytochemistry were used to characterize the expression of neurofibromin in cultured keratinocytes. RESULTS: All neurofibromin-specific Ab immunolabeled the epidermis. The basal keratinocytes displayed the most prominent immunosignal for type II neurofibromin. RT-PCR demonstrated the presence of both type I and II neurofibromin mRNA transcripts in cultured keratinocytes. Keratinocytes induced to differentiate and to arrest division by a high (1.4 mM) Ca2+ concentration of the culture medium displayed a down-regulation of neurofibromin expression at the mRNA and protein levels. This was most strikingly demonstrated by a reduction of immunoreactivity for type II neurofibromin. Basal cell carcinomas displayed a weak immunosignal for type II neurofibromin. In contrast, particularly the central areas of squamous cell carcinoma, islands were intensely immunolabeled. CONCLUSIONS: The results suggest that neurofibromin acts as a regulator of the basal keratinocytes in normal skin and that cultured keratinocytes offer a human model for studies aimed to elucidate the regulation of neurofibromin gene expression. Furthermore, aberrations in neurofibromin expression may play a role in the pathogenesis of epidermal cancers.

Amino Acid Sequence↗

PubMed1994

Pachydermoperiostosis: analysis of the connective tissue abnormality in one family.

BACKGROUND: Pachydermoperiostosis (PDP) is a rare hereditary disease characterized by hyperostosis, clubbing of fingers, coarse skin, and abnormalities in other organs, such as the gastrointestinal tract. Previous studies have disclosed several abnormalities in the connective tissue in these patients. OBJECTIVE: The purpose of the study was to investigate connective tissue abnormalities in one family with PDP. METHODS: Clinical features were evaluated; x-ray, immunohistochemical, and electronmicroscopic studies were performed; and markers of collagen metabolism and lysosomal enzymes were determined. RESULTS: Immunohistochemical and ultrastructural studies revealed accumulation of tenascin, glycosaminoglycans, and fibrillar material in apparently disorganized microfibrils of elastic fibers. Osteocalcin levels in the serum were increased, but synthesis and degradation markers of collagen in the serum were not altered. No evidence of a lysosomal enzyme deficiency was found. CONCLUSION: Acidic mucopolysaccharides and some fibrillar material accumulate in the dermis of patients with PDP. Increased levels of osteocalcin in serum indicate higher osteoblastic activity. Markers of synthesis and degradation of collagen were not altered.

Acid Phosphatase↗

PubMed1994

Systemic glucocorticoids decrease the synthesis of type I and type III collagen in human skin in vivo, whereas isotretinoin treatment has little effect.

The effects of systemic glucocorticoid and isotretinoin treatments on type I and type III collagen synthesis in intact skin were investigated by measuring the carboxyterminal and aminoterminal propeptides of type I procollagen, and the aminoterminal propeptide of type III procollagen, in suction blister fluid (SBF), in a study of 27 patients. All three parameters were significantly lower in the SBF of glucocorticoid-treated patients than in controls or patients undergoing treatment with isotretinoin, whereas the latter two groups did not differ significantly from each other. During glucocorticoid treatment, the concentrations of the procollagen propeptides were only about 20% of the corresponding control values, indicating that systemic therapy with prednisone at a dose of 0.48 mg/kg per day almost totally abolishes collagen synthesis in the skin. These results indicate that systemic glucocorticoid treatment suppresses the synthesis of both type I and type III collagen in the dermis, and suggest that many side-effects of these drugs, such as atrophy of the skin, are due to this inhibition. Systemic isotretinoin treatment did not stimulate skin collagen synthesis. Thus, its regenerative effect on connective tissue may be mediated by mechanisms other than direct stimulation of collagen synthesis.

Adult↗

PubMed1994

Aberrant accumulation of p53 associates with Ki67 and mitotic count in benign skin lesions.

Sixty-two skin samples from patients with a variety of benign disorders (20 cases of psoriasis, 14 cases of chronic dermatitis, 11 seborrhoeic keratoses, 11 cases of lichen planus), and seven normal skin samples, were stained immunohistochemically with a polyclonal antibody (CM-1) to p53, and a monoclonal antibody to Ki67, using the avidin-biotin complex method. p53-positive keratinocytes could be found in most of these lesions. The percentage of p53-positive cells was, however, far lower than usually seen in p53-positive malignant tumours. No p53 reactivity was observed in the normal skin samples. Variable Ki67 reactivity was observed in all skin samples. Overall, the number of Ki67-positive cells was higher in skin samples in which the proportion of p53-positive cells was high (> 0.5% of total epidermal cell population) (P = 0.004). This also applied separately to psoriatic and non-psoriatic lesions (P = 0.028 and P = 0.033, respectively). In cases with > 10% of Ki67-positive cells, there were significantly more mitoses (P < 0.001). This association applied to both psoriasis and the other lesions studied (P = 0.024 and P < 0.001, respectively). The results show that immunohistochemically detectable accumulation of p53 is a frequent finding in non-neoplastic skin lesions. As p53 positivity was associated with the proliferation marker Ki67, the accumulation of p53 is possibly a response to an increased proliferation rate of the keratinocytes in these skin diseases, or alternatively it may be associated with apoptosis.

Betamethasone↗

PubMed1994

72 KD and 92 KD type IV collagenase, type IV collagen, and laminin mRNAs in breast cancer: a study by in situ hybridization.

It is widely accepted that basement membrane (BM) components are synthesized by epithelial cells and that production of BM-degrading proteases by cancer cells is necessary for invasive growth. In this study we used nucleic acid in situ hybridization (ISH) to investigate the presence of mRNAs for 72 KD and 92 KD Type IV collagenase, alpha 1 (IV) chain of Type IV collagen, and laminin B1 chain in 20 breast carcinomas of various histological types. The mRNA signals for 72 KD Type IV collagenase, Type IV collagen, and laminin were much more abundant in stromal fibroblasts and endothelial cells than in carcinoma cells. The signal for 92 KD Type IV collagenase mRNA was strong in carcinoma cells and considerably weaker in stromal fibroblasts and endothelial cells. Labeling for 72 KD and 92 KD Type IV collagenase mRNA was also found in benign fibroadenomas and for 92 KD Type IV collagenase in non-neoplastic ducts and acini. The results indicate that stromal cells have a more important role in the synthesis and degradation of BMs in breast carcinomas than previously thought and that production of these enzymes is not restricted to malignancy.

Adult↗

PubMed1994

UV irradiation induces the expression of gelatinases in human skin in vivo.

UV irradiation results in marked changes in skin connective tissue, such as degeneration of collagen, and abnormal elastosis. The mechanism of connective tissue damage by UV has not been clarified in detail. In the present study the mechanism of actinic damage was studied by assaying gelatinases, 72-kDa (MMP-2) and 92-kDa (MMP-9), from suction blister fluids induced on patients who had received either UVB or PUVA treatments. The results indicate that both UVB and PUVA increase the levels of gelatinases in human skin. By in situ hybridization, it was also possible to show that UV irradiation induced increased levels of gelatinase mRNAs in fibroblasts. Furthermore, in samples from severe actinic damage, gelatinase mRNAs were abundantly present, suggesting that gelatinases may contribute to photodamage.

Adult↗

PubMed1994

Interleukin 1 alpha (IL-1 alpha) in human skin in vivo: lack of correlation to markers of collagen metabolism.

Levels of interleukin 1 alpha (IL-1 alpha) were studied from blister fluids collected from 14 patients with various types of blistering diseases. In all the fluids, IL-1 alpha could be detected, the concentrations varying from 5 to 1730 pg/ml. For comparison IL-1 alpha was also assayed from suction blisters of 13 subjects; 8 atopic patients and 5 healthy controls. IL-1 alpha was also present in suction blisters in measurable quantities, suggesting that during suction IL-1 alpha is released into the blister cavity. Since IL-1 alpha has been shown to have marked effects on collagen metabolism, the marker of collagen synthesis (carboxyterminal propeptide of type I procollagen (PICP)) and gelatinase were assayed from the same samples. There was no apparent correlation between the levels of IL-1 alpha, PICP or gelatinase in blister fluids. The possible association of IL-1 alpha and collagen metabolism was further studied in experimental conditions. Topical glucocorticoid markedly decreased the level of PICP in suction blisters but did not have any significant effect on IL-1 alpha. UVB-radiation, on the other hand, caused increase in IL-1 alpha but did not have any profound effect on collagen metabolism. During the re-epithelialization of the blister floor the level of IL-1 alpha decreased markedly, and at the same time the expression of gelatinase was increased. The results indicate that IL-1 alpha is released in large quantities into blister fluid when using the suction blister model. However, no apparent correlation could be observed in healthy or diseased skin between the levels of IL-1 alpha, collagen synthesis marker or gelatinase.

Administration, Topical↗

PubMed1994

Collagen synthesis in human skin in vivo: modulation by aging, ultraviolet B irradiation and localization.

The effect of aging, sex, skin location and a short whole body ultraviolet B (UVB) phototherapy on type I and type III skin collagen synthesis were studied by measuring carboxy- and aminoterminal propeptides of type I and aminoterminal propeptide of type III procollagens (PICP, PINP and PIIINP, respectively) in suction blister fluid (SBF). The concentrations of PICP and PIIINP correlated negatively with age in the material of 30 men and 27 women (age range 23-86 years, mean age 51 years). As the subjects were divided into 3 age groups (23-34, 35-54 and 55-86 years) and the mean concentrations of the procollagens were compared between the groups, the youngest age groups in men and in the whole material had significantly higher concentrations than the two older age groups. These results confirm the previous results, which have shown by other methods that skin collagen synthesis decreases during aging. SBF was also obtained from 4 different body regions (back, arm, abdomen and leg) of 5 young male subjects and from 2 different body regions (abdomen and thigh) of 9 older subjects. Wide individual range in the concentrations of PICP, PINP and PIIINP was noticed but, in general, none of the body regions seemed to have more excessive collagen synthesis than the other ones. SBF was further collected from abdominal skin of 8 young male dermatological patients receiving UVB phototherapy. When the concentrations of PICP and PIIINP in SBF obtained before the treatment, after the treatment and from the covered control area were compared no statistical differences were noted, suggesting that short UVB treatment has no effect on skin collagen synthesis in vivo.

Abdomen↗

PubMed1994

Aging of the skin connective tissue: how to measure the biochemical and mechanical properties of aging dermis.

The connective tissue of the skin is composed mostly of collagen and elastin. Collagen makes up 70-80% of the dry weight of the skin and gives the dermis its mechanical and structural integrity. Elastin is a minor component of the dermis, but it has an important function in providing the elasticity of the skin. During aging, the synthesis of collagen gradually declines, and the skin thus becomes thinner in protected skin, especially after the seventh decade. Several factors contribute to the aging of the skin. In several hereditary disorders collagen or elastin are deficient, leading to accelerated aging. In cutis laxa, for example, elastin fibers are deficient or completely lacking, leading to sagging of the skin. Solar irradiation causes skin to look prematurely aged. Especially ultraviolet radiation induces an accumulation of abnormal elastotic material. These changes are usually observed after 60 years of age, but excessive exposure to the sun may cause severe photoaging as early as the second decade of life. The different biochemical and mechanical parameters of the dermis can be studied by modern techniques. The applications of these techniques to study the aging of dermal connective tissue are described in detail.

Adult↗

PubMed1993

Serum markers of collagen synthesis and degradation in skin diseases. Altered levels in diseases with systemic manifestation and during systemic glucocorticoid treatment.

Serum concentrations of the markers of collagen synthesis and degradation, collagen I propeptide (PICP), collagen III propeptide (PIIINP) and the cross-linked telopeptide of type I collagen (ICTP) were measured in young male dermatological patients and in control subjects. No significant differences were noted between patients suffering from atopic eczema (n = 24), other eczemas (n = 11), acne (n = 8), psoriasis (n = 7) or tinea (n = 9) and the control subjects (n = 24). In the total study population representing patients with common skin diseases and control subjects there was a significant correlation between the serum concentrations of PICP and PIIINP and between the concentrations of PICP and ICTP. This suggests that synthesis of type I and III collagens in vivo is coordinated and that the degradation and synthesis of type I collagen is balanced. These markers were also measured in older patients suffering from psoriasis, eczema and various connective tissue diseases. It was noted that the degree of skin involvement in these diseases was not related to the serum concentrations of the markers of collagen metabolism. The highest levels of PICP and PIIINP were observed in a patient with systemic mastocytosis (PICP 309 micrograms/l and PIIINP 8.0 micrograms/l). Increased levels of PIIINP were also found in patients with a high alcohol consumption. We have previously demonstrated that systemic glucocorticoids reduce collagen propeptide levels in serum. In the present study we also proved that systemic glucocorticoids have no effect on collagen degradation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1993

Collagen synthesis in intact skin is suppressed during wound healing.

OBJECTIVE: Simultaneous monitoring of total collagen synthesis as well as synthesis in intact skin and in the wound to verify the higher priority of wound healing after surgery. SUMMARY BACKGROUND DATA: Synthesis of acute phase proteins is stimulated by surgical trauma. At the same time, production of albumin is inhibited and there is a net catabolism of skeletal muscle proteins. Similarly, the authors have found a transient inhibition of total collagen synthesis after surgery. The authors hypothesized a lower priority in synthesis of structural and peripheral collagen for the benefit of wound healing. METHODS: The concentrations of the carboxyterminal propeptide of type I procollagen (PICP) and the aminoterminal propeptide of type III procollagen (PIIINP) were measured in suction blister fluid of intact skin and in wound fluid in ten surgical patients. PICP and PIIINP concentrations in serum were also measured. Specific radioimmunoassays were used. RESULTS: In peripheral skin, the median preoperative concentrations of PICP and PIIINP were 228 and 140 micrograms/L, respectively. On postoperative days 1, 2, 4 and 7, the median concentration of PICP was 145 (p = 0.01, Wilcoxon signed rank sum test), 102 (0.02), 159 (0.03), and 152 (0.06) micrograms/L, respectively. The postoperative medians of PIIINP were 68 (p = 0.17), 76 (0.04), 66 (0.06), and 56 (0.03) micrograms/L, respectively. At the same time, collagen synthesis in the wound increased dramatically from the second day on. After an initial decrease, propeptide concentrations in serum gradually increased from the fourth day on. CONCLUSIONS: Collagen synthesis is regulated for the benefit of the wound during the acute phase response.

Acute-Phase Reaction↗

PubMed1993

Demonstration of 72-kDa and 92-kDa forms of type IV collagenase in human skin: variable expression in various blistering diseases, induction during re-epithelialization, and decrease by topical glucocorticoids.

Type IV collagenases have been shown to play an important role in tumor metastasis and wound healing. In the present study, we have demonstrated the presence of 72-kDa and 92-kDa forms of type IV collagenase in human skin by biochemical and in situ hybridization techniques. In situ hybridization allowed us to localize the 72-kDa form mostly to fibroblasts and the 92-kDa form to the epidermis and endothelial cells. The presence of type IV collagenase was confirmed by Western blotting. Enzyme activity was assayed in spontaneous blisters (18 subjects) and suction-induced blisters (29 subjects) by the zymography method, and by using type IV collagen as the substrate. Thus, it was possible to detect both the 92-kDa and 72-kDa forms in spontaneous and induced blisters. An especially high level of the 92-kDa enzyme was found in a bullous pemphigoid patient. Type IV collagenases were studied during re-epithelialization of the blister, using the suction-blister model. There was a marked induction of the 92-kDa type that was confirmed to be in the regenerating, migratory, epithelium by in situ hybridization studies. These results indicate that 92-kDa type IV collagenase may play an essential role in the normal physiology and integrity of the skin and may be an important regulator of re-epithelialization. It was also shown that potent topical glucocorticoid down-regulated the 92-kDa type collagenase, suggesting that glucocorticoids may have a beneficial role in some skin diseases by decreasing type IV collagenase activity and, thus, reducing tissue destruction.

Administration, Topical↗

PubMed1993

Effects of systemic isotretinoin on serum markers of collagen synthesis and degradation.

In the present investigation, collagen synthesis and degradation were studied by measuring the carboxyterminal propeptide of type I procollagen (PICP), the aminoterminal propeptide of type III procollagen (PIIINP) and a type I collagen-specific degradation peptide (ICTP) in the sera of 43 male patients, treated for acne with isotretinoin or with tetracycline. The values were compared with those observed in 24 acne patients without treatment and in healthy controls. The treatment with isotretinoin did not seem to affect these parameters in a cross-sectional setting, whereas tetracycline treatment was associated with slightly decreased levels of ICTP. Since there were marked variations in the PICP, PIIINP and ICTP levels between individual subjects, a follow-up study, including male and female patients, others than in the first part of the study, was conducted. Two other biochemical markers of bone metabolism, osteocalcin, reflecting osteoblastic activity, and tartrate-resistant acid phosphatase (TRAP), reflecting osteoclastic activity, were also analyzed. In females, all these parameters were lower than in males. In addition, the changes in females were more pronounced; in particular, PIIINP and TRAP were significantly increased in females during retinoid treatment (p < 0.05 and p < 0.01, respectively). Importantly, no increase was found in the synthesis of type I collagen during retinoid treatment, suggesting that the commonly used retinoid dosages do not stimulate the synthesis of type I collagen in vivo.

Acne Vulgaris↗

PubMed1993

Expression of 72 kilodalton and 92 kilodalton type IV collagenase in malignant fibrous histiocytomas and dermatofibromas.

BACKGROUND: In previous studies, it has been shown that the stromal cells of epithelial tumors are capable of synthesizing 72 and 92 kilodalton (kd) type IV collagenase mRNA. The mRNA synthesis of these collagenases in mesenchymal tumors has not been extensively studied, however. This study was undertaken to explore the synthesis of 72 and 92 kd type IV collagenase mRNAs in malignant and benign fibrous histiocytomas and its correlation with the known biologic behavior of these tumors. EXPERIMENTAL DESIGN: The synthesis of 72 kd and 92 kd type IV collagenase mRNA was studied in 10 malignant fibrous histiocytomas (MFHs) and 7 dermatofibromas using in situ hybridization methods. The tumors were also studied with a commercial monoclonal antibody to the 72 kd type IV collagenase. Additionally, three dermatofibromas were studied with an antibody to the 92 kd type IV collagenase. The media of three cell lines (MFH, dermatofibroma and skin fibroblast cell line) were also analyzed by zymography assay. RESULTS: The results revealed mRNA for the 72 kd and 92 kd collagenases in tumor cells of both MFHs and dermatofibromas. Also intracytoplasmic immunoreactivity for the 72 kd type IV collagenase could be seen in all the tumors. In the zymography assay, 72 kd type IV collagenase activity was detected in the culture media of all the cell lines tested, but activity for the 92 kd enzyme was only seen in the MFH. However, immunoreactivity for the antibody to the 92 kd type IV collagenase was also seen in dermatofibromas. CONCLUSIONS: The findings indicate that MFHs and dermatofibromas produce type IV collagenases. The synthesis of the mRNAs for both 72 kd and 92 kd type IV collagenase was quantitatively similar in MFHs and dermatofibromas indicating that there is no correlation between the biologic behavior of the tumors and the synthesis of these substances. Therefore, additional factors other than synthesis of type IV collagenases by tumor cells, must be involved in the process of spread and invasion of tumor cells into the neighbouring tissues.

Aged↗