Familial aggregation in multiplex families with CNS cancers was mainly attributed to neurofibromatosis and in colorectal cancer to FAP- and HNPCC-syndromes.
The aim of this study was to evaluate the cytomorphologic maturity and molecular activation of cancer-associated fibroblasts (CAFs) in the intratumoral stroma and invasive front in colorectal cancer and understand how they affect cancer invasion and long-term oncological outcomes.The cytomorphologic maturity of and α-smooth muscle actin (α-SMA), fibroblast activation protein α (FAPα), and fibroblast-specific protein 1 (FSP-1) expression in CAFs in the intratumoral stroma (CAF) and the invasive front (CAF) of colorectal cancer tissues were compared (n = 147).
This "surrogate analyte" approach was applied to measure the Pirc (an Apc-mutant rat kindred that models human FAP) mucosa and polyps PGE<sub>2</sub>, one of the strong biomarkers of colorectal cancer.
To detect the effects of FAP-α on human umbilical vein endothelial cells (HUVECs), conditioned medium (CM) from CRC cell lines was used and it was identified that CM from SW1116 cells with overexpressed FAP-α exhibited significantly increased VEGF-R2, phosphorylated extracellular signal-regulated kinase (p-ERK) and p-RAC-α serine/threonine-protein kinase (Akt) in HUVECs, in addition to the proliferation rate.
Taken together, our study suggested that high FAP expression in CAFs is one reason leading to immune checkpoint blockades resistance in CRC patients and FAP is an optional target for reversing immune checkpoint blockades resistance.
A subset of APC mutation carriers shows a milder familial adenomatous polyposis phenotype (attenuated FAP) developing smaller number of polyps and colorectal cancer at an older age.
Familial adenomatous polyposis [FAP (OMIM 175100)] is an autosomal dominant colorectal cancer predisposition syndrome characterized by hundreds to thousands of colonic polyps and, if untreated by a combination of screening and/or surgical intervention, an approximately 99% lifetime risk of colorectal cancer.
To better delineate the role of mucosal immunity in colorectal cancer, we evaluated the efficacy of intrarectal recombinant vaccinia virus expressing the human carcinoembryonic Ag (CEA) in a murine FAP model in which mice are predisposed to colorectal cancer and also express human CEA in the gut.
Since the genetic basis of CRC in FAP and in sporadic CRC is similar, intervention trials in FAP gene carriers provide an attractive strategy for investigation of potential chemo-preventive agents, since smaller numbers of subjects and shorter time frames are needed.
We have demonstrated the utility of this strategy in two different hereditary colorectal cancer syndromes, one caused by a defective tumour suppressor gene on chromosome 5 (familial adenomatous polyposis, FAP) and the other caused by a defective mismatch repair gene on chromosome 2 (hereditary non-polyposis colorectal cancer, HNPCC).
These results suggest that the mechanism by which colorectal carcinomas lose genetic material on chromosome 5 can affect this functional gene located distally to the FAP gene.
This parallels the assignment of the FAP gene to chromosome 5 (see accompanying paper) and suggests that becoming recessive for this gene may be a critical step in the progression of a relatively high proportion of colorectal cancers.