Marker profiling of normal keratinocytes identifies the stroma from squamous cell carcinoma of the oral cavity as a modulatory microenvironment in co-culture

Abstract

Tumor-derived stromal fibroblasts acquire distinct properties to shape a microenvironment conducive to altering the phenotypic characteristics of normal epithelial cells in vitro.

Origin of carcinoma associated fibroblasts

“…Yet, spontaneous cross talk between epithelial and stromal cells induces the expression of genes in both the stroma and cancer cells. [63][64][65][66][67][68][69][70][71] These genes include classical cancer stroma markers that reportedly may promote oncogenic potential of adjacent epithelia. 2,3,[72][73][74] This is possibly due to the late presentation with carcinoma disease in human life span.…”

“…[115][116][117][118] The fibroblast response is hardwired in the genome as part of the cancer's resemblance to a chronic wound, aiming at support of epithelial cell survival and expansion. [119][120][121][122][123][124][125][126][127][128] In addition to parsimony, this hypothesis offers clear predictions to scientifically test against corresponding null hypotheses; (1) That co-culture of cancer cells with normal fibroblasts will induce expression of CAF-specific genes in the fibroblasts, [63][64][65][66][67][68][69][70][71] [63][64][65][66][67][68][69][70][71] Many of the genes shown to be activated in these co-cultures are known markers of CAFs in vivo, such as MMP1, MMP3, collagens, TNC, etc. Evidence that this reciprocal interaction promotes cancer includes the anti-cancer effect of Imatinib, on carcinoma animal models.…”

Human hair follicle and interfollicular keratinocyte reactivity to mouse HPV16-transformed cells: An in vitro study

“…normal hair follicle (NHF) and normal interfollicular epidermal (NIF) keratinocytes, cultured under the influence of TC-1 cells was monitored and compared with the phenotype of the same cells cultured on a mouse 3T3 cell standard feeder (29). These cells are also of mouse origin and are known to support the growth and physiological differentiation pattern in the normal human keratinocytes under in vitro conditions (22,23).…”

“…The impact of stromal cells on the tumor elements was observed predominantly in breast (18), prostate gland (19,20) and colon cancer (21). The fibroblasts isolated from basal or squamous cell carcinoma are able to influence significantly the phenotype of cocultured normal interfollicular keratinocytes to be similar to the phenotype of malignant epithelial tumor cells from which the ONCOLOGY REPORTS 20: 75-80, 2008 75 Human hair follicle and interfollicular keratinocyte reactivity to mouse HPV16-transformed cells: An in vitro study stromal cells were prepared (22,23). Although the molecular mechanism of the stromal cell action to cancer cells is not clear, the role of specific growth factors/cytokines can be expected because the direct contact between stromal and epithelial cells is not necessary (22,23).…”

“…The fibroblasts isolated from basal or squamous cell carcinoma are able to influence significantly the phenotype of cocultured normal interfollicular keratinocytes to be similar to the phenotype of malignant epithelial tumor cells from which the ONCOLOGY REPORTS 20: 75-80, 2008 75 Human hair follicle and interfollicular keratinocyte reactivity to mouse HPV16-transformed cells: An in vitro study stromal cells were prepared (22,23). Although the molecular mechanism of the stromal cell action to cancer cells is not clear, the role of specific growth factors/cytokines can be expected because the direct contact between stromal and epithelial cells is not necessary (22,23). The nature of tumor-associated fibroblasts is not clear as yet, but in principle they can arise from three different mechanisms or their combination: i) the cytokine/growth factors produced by the malignant cells can influence the local fibroblast population that will consequently support the growth of cancer cells (21); ii) the cancer cells can fuse with the local fibroblasts and form polyploid stromal elements (24) and iii) the direct formation of stromal fibroblasts by the epithelial-mesenchymal transition of malignant epithelium to fibroblastoid stromal cells (25).…”