The cancer-inhibitory effects of proliferating tumor-residing fibroblasts.

Initiation, local progression, and metastasis of cancer are associated with specific morphological, molecular, and functional changes in the extracellular matrix and the fibroblasts within the tumor microenvironment (TME). In the early stages of tumor development, fibroblasts are an obstacle that cancer cells must surpass or nullify to progress. Thus, in early tumor progression, specific signaling from cancer cells activates bio-pathways, which abolish the innate anticancer properties of fibroblasts and convert a high proportion of them to tumor-promoting cancer-associated fibroblasts (CAFs). Following this initial event, a wide spectrum of gene expression changes gradually leads to the development of a stromal fibroblast population with complex heterogeneity, creating fibroblast subtypes with characteristic profiles, which may alternate between being tumor-promotive and tumor-suppressive, topologically and chronologically in the TME. These fibroblast subtypes form the tumor's histological landscape comprising areas of cancer growth, inflammation, angiogenesis, invasion fronts, proliferating and non-proliferating fibroblasts, cancer-cell apoptosis, fibroblast apoptosis, and necrosis. These features reflect general deregulation of tissue homeostasis within the TME. This review discusses fundamental and current knowledge that has established the existence of anticancer fibroblasts within the various interacting elements of the TME. It is proposed that the maintenance of fibroblast proliferation is an essential parameter for the activation of their anticancer capacity, similar to that by which normal fibroblasts would be activated in wound repair, thus maintaining tissue homeostasis. Encouragement of research in this direction may render new means of cancer therapy and a greater understanding of tumor progression.

Role of stromal fibroblasts in cancer: promoting or impeding?

The basement membrane, immune cells, capillaries, fibroblasts and extracellular matrix (ECM) constitute the tumour stroma, commonly referred to as the 'reactive stroma'. The fibroblasts from the initial stages of a tumour, as the main constituents of the reactive stroma, present a different phenotype from the normal fibroblasts and play a crucial role in tumour progression. This review presents the differences between normal and tumour stromal fibroblasts and analyzes the molecular mechanisms (which involve growth factors, ECM components, matrix metalloproteinases, integrins and cell adhesion molecules) in the complex interactions between stromal fibroblasts and tumour cells. To date, several examples of heterotypic interactions between tumour stromal fibroblasts and tumour cells have supported the hypothesis that the tumour stroma promotes the growth of the tumour mass, as well as invasion and metastasis. However, it remains possible that the stroma acts essentially as a local modulator to impede tumorigenesis at an early stage and that the desmoplastic response is a host defence reaction designed to confine the developing tumour. The latter hypothesis has largely been neglected. The review aims to give a broader view on the role of stromal fibroblasts in tumour growth, invasion and metastasis.

Invasive carcinomas may arise in colorectal adenomas with high-grade dysplasia and with carcinoma in situ.

Colorectal carcinomas (CRC) usually arise in colorectal adenomas (CRA) displaying high-grade dysplasia (HGD) or carcinoma in situ (CIS). The aim was to assess the frequency of adenomas displaying HGD or CIS in a cohort of consecutive CRA with submucosal invasive carcinoma. Ninety-two consecutive adenomas were investigated. Sub-mucosal invasion was present in the 39 adenomas with HGD (42%) and in 58% (53/92) of the adenomas with CIS (p<0.05). Sections from 49 adenomas were stained with the DNA-specific Feulgen reaction and for the proliferation marker Ki-67. Five consecutive high power fields (HPFs) were evaluated using a x40 objective. Marked Feulgen reaction was recorded in 91.8% or in 101 of the 110 HPFs studied in adenomas with HGD, but in none of the 135 HPFs studied in adenomas with CIS (p<0.05). Intense Ki-67 expression (>/=75%) was present in 98.2% or in 108 of the 110 HPFs studied in adenomas with HGD, but only in 1.4% or in 2 of the 135 HPFs in adenomas with CIS (p<0.05). Hence, HGD cells and CIS cells can be differentiated not only morphologically but also chemically by the semi-quantitative appreciation of their DNA content and immunohistochemically by the apparent difference in cell proliferation. Although submucosal invasion occurred significantly more frequently in adenomas with CIS than in those with HGD, as many as 42% of the adenomas with submucosal invasion displayed HGD at histology. Despite morphological, chemical and immunohistochemical dissimilarities, these 2 non-invasive neoplasias might have similar biological behaviour in terms of progression towards submucosal invasion.