TGF‐β‐induced IGFBP‐3 is a key paracrine factor from activated pericytes that promotes colorectal cancer cell migration and invasion

Abstract

The crosstalk between cancer cells and the tumor microenvironment has been implicated in cancer progression and metastasis. Fibroblasts and immune cells are widely known to be attracted to and modified by cancer cells. However, the role of pericytes in the tumor microenvironment beyond endothelium stabilization is poorly understood. Here, we report that pericytes promoted colorectal cancer (CRC) cell proliferation, migration, invasion, stemness, and chemoresistance in vitro, as well as tumor growth in a xenograft CRC model. We demonstrate that coculture with human CRC cells induced broad transcriptomic changes in pericytes, mostly associated with TGF-β receptor activation. The prognostic value of a TGF-β response signature in pericytes was analyzed in CRC patient data sets. This signature was found to be a good predictor of CRC relapse. Moreover, in response to stimulation by CRC cells, pericytes expressed high levels of TGF-β1, initiating an autocrine activation loop. Investigation of secreted mediators and underlying molecular mechanisms revealed that IGFBP-3 is a key paracrine factor from activated pericytes affecting CRC cell migration and invasion. In summary, we demonstrate that the interplay between pericytes and CRC cells triggers a vicious cycle that stimulates pericyte cytokine secretion, in turn increasing CRC cell tumorigenic properties. Overall, we provide another example of how cancer cells can manipulate the tumor microenvironment.

Transforming Growth Factor-β: A Multifunctional Regulator of Cancer Immunity

“…The TGF-β family of cytokines consists of three different isoforms, TGF-β1, TGF-β2, and TGF-β3, with each of them having a unique expression mode and executing distinct functions. For example, TGF-β2 can deplete interleukin 6 (IL-6) function and induce apoptosis [1], TGF-β3 affects the differentiation of mesenchymal stromal cells (MSCs) [2], while TGF-β1 plays an important role in cancer progression and tumour microenvironment (TME) development [3,4].…”

Re-Clustering and Profiling of Digestive System Tumors According to Microenvironment Components

“…In recent years, more and more research has focused on the importance of the tumor microenvironment in driving malignancy, including in digestive system tumors ( 9 – 12 ). Most of the previous studies have only focused on tumor cells themselves and their internal mechanisms, but mutual communication and regulation exist between tumor cells and other components of their microenvironment ( 13 – 15 ). Through paracrine mechanisms, tumor cells could reprogram their surrounding immune and stromal microenvironments into a “pro-tumor” microenvironment.…”

From Proteomic Mapping to Invasion-Metastasis-Cascade Systemic Biomarkering and Targeted Drugging of Mutant BRAF-Dependent Human Cutaneous Melanomagenesis

“…The IGFBP3 /IBP3 (16.79) and IGFBP5 /IBP5 (3.51) members of the insulin-like growth factor-binding protein family are also presented with a WM266-4-specific expression patterning ( Table S3 ), likely deregulating the bioavailability and signaling power of their cognate insulin-like growth factors (IGFs). IBP3 upregulation has been tightly associated with brain metastasis in lung adenocarcinoma [ 86 ], tumor metastasis in nasopharyngeal carcinoma [ 87 ], and TGF-β-dependent colorectal cancer cell migration and invasion [ 88 ]. Hence, it seems that IBP3 may act as principal metastatic driver in BRAF V600D melanoma cell environments, with its targeted drugging presumably offering new opportunities for successful management of the advanced disease.…”