Cancer microenvironment is created not only by malignant epithelial cells, but also by several kinds of stromal cells. Since Paget proposed the “seed and soil” hypothesis, the biological importance ...of the cancer microenvironment has come to be widely accepted. The main compartment of host stromal cells are fibroblasts (Cancer-Associated Fibroblasts; CAFs), which are the main source of the collagen-producing cells. CAFs directly communicate with the cancer cells and other types of stromal cells to acquire a specific biological phenotype. CAFs play important roles in several aspects of the tumor progression process and the chemotherapeutic process. However, CAFs have heterogeneous origins, phenotypes, and functions under these conditions. A crucial challenge is to understand how much of this heterogeneity serves different biological responses to cancer cells. In this review, we highlight the issue of how diverse and heterogeneous functions given by CAFs can exert potent influences on tumor progression and therapeutic response. Furthermore, we also discuss the current advances in the development of novel therapeutic strategies against CAFs.
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Podoplanin (PDPN) is a transmembrane receptor glycoprotein that is upregulated on transformed cells, cancer associated fibroblasts and inflammatory macrophages that contribute to cancer progression. ...In particular, PDPN increases tumor cell clonal capacity, epithelial mesenchymal transition, migration, invasion, metastasis and inflammation. Antibodies, CAR‐T cells, biologics and synthetic compounds that target PDPN can inhibit cancer progression and septic inflammation in preclinical models. This review describes recent advances in how PDPN may be used as a biomarker and therapeutic target for many types of cancer, including glioma, squamous cell carcinoma, mesothelioma and melanoma.
Podoplanin (PDPN) is a transmembrane receptor glycoprotein that is upregulated on transformed cells, cancer associated fibroblasts (CAFs), and inflammatory macrophages that contribute to cancer progression. This review describes recent advances in how PDPN may be used as a biomarker and therapeutic target for many types of cancer including glioma, squamous cell carcinoma, mesothelioma, and melanoma.
Cancer tissue comprises not only cancer cells, but also several types of non-cancerous cells, such as cancer-associated fibroblasts. These fibroblasts directly and/or indirectly communicate with the ...cancer cells and other types of stromal cells, to create a specific tumor microenvironment. Cytotoxic chemotherapy plays a central role in treating cancer; however, tumor re-progression (recurrence) is a significant problem for cancer patients. Cytotoxic anticancer drugs act on fibroblasts as well as cancer cells and, after chemotherapy, all surviving cells are in contact with one another in the local environment. Therefore, an understanding of the molecular interactions between surviving cancer cells and fibroblasts is necessary to prevent tumor re-progression and to sustain the effect of cytotoxic agents. After chemotherapy, the number of fibroblasts may increase, some of which are identifiable as tumor-promoting. In this review, we discuss the significance of cancer-associated fibroblasts in tumor re-progression after chemotherapy, and the potential value of targeting them to enhance clinical outcomes.
Immune checkpoint blockade has provided a paradigm shift in cancer therapy, but the success of this approach is very variable; therefore, biomarkers predictive of clinical efficacy are urgently ...required. Here, we show that the frequency of PD-1
CD8
T cells relative to that of PD-1
regulatory T (T
) cells in the tumor microenvironment can predict the clinical efficacy of programmed cell death protein 1 (PD-1) blockade therapies and is superior to other predictors, including PD ligand 1 (PD-L1) expression or tumor mutational burden. PD-1 expression by CD8
T cells and T
cells negatively impacts effector and immunosuppressive functions, respectively. PD-1 blockade induces both recovery of dysfunctional PD-1
CD8
T cells and enhanced PD-1
T
cell-mediated immunosuppression. A profound reactivation of effector PD-1
CD8
T cells rather than PD-1
T
cells by PD-1 blockade is necessary for tumor regression. These findings provide a promising predictive biomarker for PD-1 blockade therapies.
Cryoprobe is a novel transbronchial biopsy (TBB) tool that yields larger tissue samples than forceps. Pathological diagnosis and biomarker analysis, such as genetic alterations and programmed ...death‐ligand 1 (PD‐L1) expression, are paramount for precision medicine against lung cancer. We evaluated the safety and usefulness of cryoprobe TBB for lung cancer diagnosis and biomarker analysis. In this single‐center, prospective single‐arm study, patients suspected of having or diagnosed with primary lung cancer underwent cryoprobe TBB using flexible bronchoscopy after conventional forceps TBB from the same lesion. Cryoprobe TBB was performed in 121 patients. The incidence rate of severe bleeding and serious adverse events (4% 90% confidence interval: 2%‐9%) was significantly lower than the expected rate (20% with 30% threshold, P < 0.01). Combining both central and peripheral lesions, the diagnostic yield rate of cryoprobe samples was 76% and that of forceps samples was 84%. Compared with forceps TBB samples, cryoprobe TBB samples were larger (cryoprobe 15 mm2 vs forceps 2 mm2) and resulted in a larger proportion of definite histomorphological diagnosis (cryoprobe 86% vs forceps 74%, P < 0.01), larger amounts of DNA extracted from samples (median: cryoprobe, 1.60 µg vs forceps, 0.58 µg, P = 0.02) and RNA (median: cryoprobe, 0.62 µg vs forceps, 0.17 µg, P < 0.01) extracted from samples, and tended to yield greater rates of PD‐L1 expression >1% (51% vs 42%). In conclusion, cryoprobe is a safe and useful tool for obtaining lung cancer tissue samples of adequate size and quality, which allow morphological diagnosis and biomarker analysis for precision medicine against lung cancer.
In this study, cryoprobe biopsy was performed in 121 patients. The incidence rate of severe bleeding and serious adverse events was 4%. Compared with forceps biopsy samples, cryoprobe biopsy samples were larger and resulted in a larger proportion of definite histomorphological diagnoses and larger amounts of DNA/RNA extracted from samples.
Cancer‐associated fibroblasts (CAFs) communicate with cancer cells and play important roles in cancer invasion. We previously reported that local invasion of cancer cells was frequently observed in ...lung adenocarcinoma patients with podoplanin (PDPN)‐expressing CAFs. However, the underlying mechanisms of this phenomenon have remained unclear. In this study, we established a novel collagen invasion assay model in which cancer cells and CAFs were cocultured; we analyzed the mechanisms governing how cancer cell invasion was promoted by PDPN(+)CAFs. By observing the dynamic movement of both CAFs and cancer cells in the collagen matrix, we found that PDPN(+)CAFs invaded the matrix to a greater extent, with more cancer cells invading within the “tracks” created by the CAFs, compared with control CAFs. The knockdown of PDPN in CAFs decreased the invasion of both the CAFs and the cancer cells. PDPN(+)CAFs displayed a higher RhoA activity and treatment with a ROCK inhibitor cancelled the increased invasion ability of PDPN(+)CAFs and subsequently decreased the number of invaded cancer cells. After intravenous injection in the mouse tail vein, PDPN(+)CAFs invaded and promoted cancer cell invasion into the lung parenchyma, compared with control CAFs. Among the patients with lung adenocarcinoma, we observed some cases with PDPN(+)CAFs at the invasive front of the tumor. These cases predominantly exhibited pleural invasion of cancer cells, known as pathological invasiveness. Our results indicated that PDPN(+)CAFs were tumor‐promoting CAFs that lead and enhance the local invasion of cancer cells, suggesting that the invasion activity of CAFs themselves could be rate‐determining for cancer cell invasion.
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The protein podoplanin helps tumors push into the surrounding tissue, and thus may be a useful target for slowing down the disease. Cancer‐associated fibroblasts (CAFs) communicate with cancer cells and assist with invasion. In this paper, the authors report that CAFs expressing podoplanin boosted the efficiency of a lung tumor's invasion of the matrix. Knocking down podoplanin, furthermore, reduced the invasiveness of both the CAFs and the tumor cells. Finally, the authors showed that this activity relied on the Rho‐ROCK pathway, and treatment with a ROCK inhibitor stifled the cells' ability to invade.
Non-small cell lung cancer (NSCLC) has a markedly poor prognosis as it progresses, and the prognosis is still unsatisfactory even with modern treatments. Cancer is composed of not only cancer cells, ...but also stroma consisting of various cell types. Cancer-associated fibroblasts (CAFs) are a major component of the stroma and the associated tumor microenvironment (TME). Particularly, CAFs are a critical component in elucidating the biological mechanisms of cancer progression and new therapeutic targets. This article outlines the TME formed by CAFs in NSCLC.
Focusing on the TME in NSCLC, we discuss the mechanisms by which CAFs are involved in cancer progression, drug resistance, and the development of therapies targeting CAFs.
In the TME, CAFs profoundly contribute to tumor progression by interacting with cancer cells through direct contact or paracrine cytokine signaling. CAFs also interact with various other stromal components to establish a tumor-promoting immunosuppressive microenvironment and remodel the extracellular matrix. Furthermore, these effects are closely associated with drug resistance. Further elucidation of the stromal microenvironment, including CAFs, could prove to be crucial in the treatment of NSCLC.
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