S TROMA REACTION AND FIBROBLAST ACTIVATION DURING CARCINOGENESIS

1.5.1 The invasion process of cancer cells is associated with stroma reaction

The cooperation between epithelial and mesenchymal cells is essential for embryonic development and also plays an important role in pathological phenomena such as wound healing and tumor progression. It is well known that many epithelial tumors are characterized by the local accumulation of connective tissue cells and extracellular material; this phenomenon has been called the stroma reaction. Stroma reaction, also known as stromagenesis, is a host reaction of connective tissue that, when induced in cancer, produces a progressive and permissive mesenchymal microenvironment, thereby supporting tumor progression (Amatangelo MD et al. 2005). The stromal microenvironment is

complex and comprises several cell types, including fibroblasts, the primary producers of the noncellular scaffolds known as ECM. The locally activated host microenvironment (both cellular and extracellular elements) in turn modifies the proliferative and invasive behavior of the tumor cells (Liotta LA and Kohn EC 2001).

Paget first propose ‘seed and soil hypothesis’ to highlight the influence of tumor growth by interactions between malignant cells and the tumor stroma in 1889 (Paget S 1889). In ‘seed and soil hypothesis’ (Paget S 1889) of cancer biology, cancer cells are the ‘seeds’, the microenvironment is the ‘soil’; in which the

‘seeds’ must find a receptive environment (Fidler IJ 2003). The normal host microenvironment is nonpermissive for neoplastic progression, tumor-reactive stroma promotes neoplastic growth and metastasis (Chlenski A et al. 2007b).

Within the same microenvironment, vascular sprouts migrate and invade towards the tumor mass while tumor cells migrate outwards in the opposite direction (Carmeliet P and Jain RK 2000). Activation of the local invasive environment seems to create a permissive field for the malignant cells (Liotta LA and Kohn EC 2001). The presence of host cells is original considered as a reaction against the aberrant behavior of the cancer cells as a mechanical and immunological defense against the cancer cells. It was described by the pathologist as desmoplasia, inflammation and angiogenesis with accumulation of stromal fibroblasts, leukocytes and endothelial cells respectively. Recently, there is growing evidence that tumor-infiltrated host cells are recruited and diverted by the cancer cells to contribute to their malignant progression rather than to protect the host (Mueller MM and Fusenig NE 2004).

The complexity of multicellular organisms necessitates a high degree of coordination among a diverse range of specialized cell types. Maintaining this

organization requires a constant and dynamic stream of intercellular communication (Radisky DC and Bissell MJ 2004). Increasing evidence suggests that this organized exchange of information is essential for maintaining the differentiated state of cells, and that sustained disruption of key intercellular signaling pathways can predispose to malignancy (Bissell MJ and Radisky D 2001).

It is well established that cellular tumorigenic potential is profoundly influenced by the microenvironment and that malignant cells can be induced to maintain a differentiated state by growth in an appropriate tissue microenvironment (Kenny PA and Bissell MJ 2003). Throughout the entire process of cancer etiology, progression and metastasis, the microenvironment of the local host tissue can be an active participant (Liotta LA and Kohn EC 2001). The invasion process of cancer cells is associated with the generation of specific stroma, called

‘cancer-induced stroma’ (Ishii G et al. 2005). The main constituents of cancer-induced stroma are inflammatory cells, (including lymphocytes, granulocytes, macrophages, and pericytes), fibroblasts and the endothelial cells of blood and lymph vessels. Inflammatory cells and endothelial cells are recruited into cancer stroma and involved in tumor immunity (Coussens LM and Werb Z 2002) and angiogenesis, respectively (Folkman J et al. 2000). New blood and lymph vessels (Carmeliet P and Jain RK 2000), immunocytes and inflammatory cells (Opdenakker G and Van Damme J 2004) as well as stromal fibroblasts (De Wever O and Mareel M 2003) don't inhibit but rather stimulate cancer invasion and metastasis, in line with Paget's “seed” and “soil” hypothesis in 1889 (Paget S 1889).

1.5.2 Stroma reaction is characterized by the fibroblast activation

The stromal cells that surround and sustain epithelia have been viewed primarily

as a source of oxygen, nutrients, and additional growth stimuli for tumors.

Bhowmick et al. report that defective stromal cells stimulate the development of epithelial tumors, which suggests that normal stromal cells may prevent epithelia from becoming tumorigenic (Bhowmick NA et al. 2004). Fibroblasts, as the major component of stroma, are recruited and can convert into smooth muscle actin-positive fibroblasts, i.e., myofibroblasts or activated fibroblasts, during stroma reaction (Kunz-Schughart LA and Knuechel R 2002a; Kunz-Schughart LA and Knuechel R 2002b). The term “myofibroblast’ was firstly used to describe, in experimental granulation tissue of Wistar rats, fibroblastic cells with a smooth muscle cell-like morphology, a strongly developed microfilamentous apparatus and a contractile phenotype (Desmouliere A et al. 2004; Majno G et al. 1971).

Myofibroblasts appear at the invasion front during stromal changes cells sharing characteristics with fibroblasts and smooth muscle cells (De Wever O and Mareel M 2003). Myofibroblast can also produce collagens and extracellular matrix proteins in response to several extracellular stimuli.

There assumably exists a continuous cross-signaling between the epithelial and the stromal compartment in normal and in pathological situations alterations that lead to invasion. The paracrine signaling interactions between cancer cells and associated fibroblasts play important roles in tumor formation and progression (Kunz-Schughart LA and Knuechel R 2002a; Kunz-Schughart LA and Knuechel R 2002b). Stromal fibroblasts create a context that promotes tumor progression (Barcellos-Hoff MH and Ravani SA 2000). Furthermore, investigators have found evidence that the proliferative activity of stromal fibroblasts in cancer-induced stroma is closely linked to lymph node and distant organ metastasis (Hasebe T et al. 2000) and that soluble factor secretion by stromal fibroblasts influences tumor progression.

Fibroblasts within cancer stroma have a migratory and invasive capacity similar to that of cancer cells and associate with cancer cells by transmitting reciprocal signals (Ishii G et al. 2005). It is unclear who is invading whom between epithelial and mesenchymal cells. The transition from normal to invasive carcinoma is preceded by, or is concomitant with, activation of local host stroma (Liotta LA and Kohn EC 2001).