SOLID tumors are composed of two discrete but interdependent compartments: the malignant cells themselves and the stroma that they induce and in which they are dispersed.1 , 2 In tumors of epitheli...

Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing.

Granulation tissue fibroblasts (myofibroblasts) develop several ultrastructural and biochemical features of smooth muscle (SM) cells, including the presence of microfilament bundles and the expression of alpha-SM actin, the actin isoform typical of vascular SM cells. Myofibroblasts have been proposed to play a role in wound contraction and in retractile phenomena observed during fibrotic diseases. We show here that the subcutaneous administration of transforming growth factor-beta 1 (TGF beta 1) to rats results in the formation of a granulation tissue in which alpha-SM actin expressing myofibroblasts are particularly abundant. Other cytokines and growth factors, such as platelet-derived growth factor and tumor necrosis factor-alpha, despite their profibrotic activity, do not induce alpha-SM actin in myofibroblasts. In situ hybridization with an alpha-SM actin probe shows a high level of alpha-SM actin mRNA expression in myofibroblasts of TGF beta 1-induced granulation tissue. Moreover, TGF beta 1 induces alpha-SM actin protein and mRNA expression in growing and quiescent cultured fibroblasts and preincubation of culture medium containing whole blood serum with neutralizing antibodies to TGF beta 1 results in a decrease of alpha-SM actin expression by fibroblasts in replicative and non-replicative conditions. These results suggest that TGF beta 1 plays an important role in myofibroblast differentiation during wound healing and fibrocontractive diseases by regulating the expression of alpha-SM actin in these cells.

/pdf/transforming-growth-factor-beta-1-induces-alpha-smooth-1reypwtl3f.pdf

Transforming growth factor-beta 1 induces alpha-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts.

Publisher Summary This chapter describes various modes of interaction between malignant cells and stroma. Malignant cells are shown to produce various lytic enzymes, which attack the stroma or to induce fibroblasts to synthesize collagenolytic, elastolytic, and glycosaminoglycan-degrading enzymes. In some cancers tumor cells stimulate fibroblasts to produce stromal components—collagen, elastin, and glycosaminoglycans. Migration of tumor cells is partly determined by versatile adhesive glycoproteins in the stroma. Wound healing and especially fibrosis (scars) appear to be possible auxiliary factors in carcinogenesis. Stromal cells (local or generalized) may exhibit subtle alterations similar to transformed cells. Stromal alterations preceding manifest malignancy contribute to carcinogenesis. In vitro data point to intricate interdependencies between cancer cells and fibroblasts resulting in synthesis of collagenolytic enzymes. Normal ontogenesis depends on a complex of interactions between various tissues among which the stroma plays an essential role. Epithelial–stromal interactions are also important in the adult organism. In cancer growth, the microenvironmental signals constitute an essential category of influences contributing to malignancy.

Stromal involvement in malignant growth.

The molecular and cellular basis of inflammation has become a topic of great interest of late because of the association between mechanisms of inflammation and risk for cancer. Inflammatory-mediated events, such as the production of reactive oxygen species (ROS), the activation of growth factors (for wound repair), and the altering of signal-transduction processes to activate cell-proliferation (to replace necrotic/apoptotic tissue cells), events that also can occur independently of inflammation, are all considered to be components of risk for a variety of cancers. Using scar cancer of the lung as an example, mechanisms of inflammation associated with recurring infections with Mycobacterium tuberculosis are discussed in the context that they may, in fact, be the major or sole cause of a cancer. Production of ROS, prostaglandins, leukotrienes, and cytokines in pulmonary tissues is greatly enhanced due to a cell-mediated immune response against macrophages infected with M. tuberculosis. These responses lead to the extensive fibrosis associated with recurring infections, possibly leading to decreased clearance of lymph and lymph-associated particles from the infected region. They also will enhance rates of cell division by inhibiting synthesis of P21, leading to enhanced progression from G0 arrest to G1 phase, from G1 to Sphase, and from G2 to M phase of the cell cycle. By increasing rates of oxidative DNA damage and inhibiting apoptosis by enhancing synthesis of BCL-2, mutagenesis of progeny cells is enhanced, and these effects coupled with enhanced angiogenesis stimulated by COX-2 products lead to an environment that is highly conducive to tumorigenesis. Based on the evidence, it appears that but for an inflammatory response to recurring infections, some cases of scar cancer would not exist. By making appropriate lifestyle and dietary changes, a variety of anti-inflammatory effects can be produced, which should attenuate inflammation-induced risk for cancer.

Inflammation as cause for scar cancers of the lung.

Collagenolytic activity, extracted from 55 tumor and healthy corresponding intestinal control samples, was determined by 3 different assays using soluble type I and fibrillar type I and III collagen, respectively, as substrate. The enzyme extracted from tumor-digested collagen type I reconstituted fibrils and yielded the three-quarter segments characteristic for the action of one of the matrix metalloproteinases: MMP-I or mammalian collagenase. Metal-chelating agents such as EDTA and O-phenanthrolin indeed inhibited this activity. Collagenolytic activities were calculated on the basis of wet weight, total DNA and total extracted protein. Correlations were sought between levels of activity and both clinicopathological stage (Dukes' staging) and grade of histological differentiation. In all the assays applied, significant correlations were found between grade of histological differentiation and collagenolytic activity expressed as the tumor/control ratios: poorly differentiated tumors exhibited a higher tumor/control ratio than well-differentiated tumors. Also, tumors penetrating into the serosa showed a higher tumor/control ratio than tumors invading the muscularis propria only. A relation between collagenolytic activity and clinico-pathological stage was observed only if activities were calculated on a DNA basis. These results confirm a relationship between the histological appearance of a tumor and its enzymatic potential to degrade interstitial collagens.

Correlation between collagenolytic activity and grade of histological differentiation in colorectal tumors.

Immunohistopathologic and biochemical studies of different collagen types extracted from human scar carcinoma of the lungs have been carried out for definition and evaluation of which types of collagen are involved in the scarring mechanism of such tumors. Tumor homogenates treated with 0.5 M acetic acid and followed by limited proteolysis with pepsin and then by fractional salt precipitation, demonstrated that Type I collagen constitutes the major collagenous component in addition to a significant increase in Type V collagen extracted from human scar carcinoma of the lung. However, when normal membranoalveolar peripheral lung tissues were processed under the same experimental conditions, Type III and IV collagens were relatively higher. Immunohistochemical studies were carried out, and the results confirmed the data above. Furthermore, these studies demonstrated a relative localized increase in Type III collagen in the area surrounding the tumor acini, which suggested that these areas are of active and recent scar formation. This supports the current concept of the scar origin as a desmoplastic reaction of the host tissues toward the neoplastic cell growth.

Dabbous M

Papers

Collagens in scar carcinoma of the lung.