The microenvironment in mature B-cell malignancies: a target for new treatment strategies
TL;DR: A paradigm shift in the treatment of selected B-cell malignancies is anticipated, moving from targeting primarily the malignant cells toward combining cytotoxic drugs with agents that interfere with the microenvironment's proactive role.
About: This article is published in Blood.The article was published on 2009-10-15 and is currently open access. It has received 543 citations till now.
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TL;DR: The disruption of tumor microenvironment interactions and the inhibition of BCR signaling as promising therapeutic strategies in CLL are identified.
776 citations
TL;DR: The results of the reported clinical trials are reviewed and the progress and key emerging factors that may play a role in effecting tumor responses are discussed, including managing toxicities and expanding the availability of personalized cell therapy as a promising approach to all hematologic malignancies.
606 citations
TL;DR: It is demonstrated that PCI-32765 effectively inhibits CLL cell migration and survival, possibly explaining some of the characteristic clinical activity of this new targeted agent.
602 citations
TL;DR: CAL-101 displays a dual mechanism of action, directly decreasing cell survival while reducing interactions that retain CLL cells in protective tissue microenvironments, and a roadmap for future therapeutic development.
534 citations
TL;DR: The data indicate that inhibition of BTK by PCI-32765 overcomes BCR- and chemokine-controlled integrin-mediated retention and homing of malignant B cells in their growth- and survival-supporting lymph node and bone marrow microenvironment, which results in clinically evident CLL regression.
497 citations
References
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TL;DR: Fibroblasts are a key determinant in the malignant progression of cancer and represent an important target for cancer therapies.
Abstract: Tumours are known as wounds that do not heal - this implies that cells that are involved in angiogenesis and the response to injury, such as endothelial cells and fibroblasts, have a prominent role in the progression, growth and spread of cancers. Fibroblasts are associated with cancer cells at all stages of cancer progression, and their structural and functional contributions to this process are beginning to emerge. Their production of growth factors, chemokines and extracellular matrix facilitates the angiogenic recruitment of endothelial cells and pericytes. Fibroblasts are therefore a key determinant in the malignant progression of cancer and represent an important target for cancer therapies.
4,232 citations
TL;DR: Using a coimplantation tumor xenograft model, it is demonstrated that carcinoma-associated fibroblasts extracted from human breast carcinomas promote the growth of admixed breast carcinoma cells significantly more than do normal mammaries derived from the same patients.
3,373 citations
TL;DR: Macrophages within the tumor microenvironment facilitate angiogenesis and extracellular-matrix breakdown and remodeling and promote tumor cell motility and are an important drug target for cancer therapy.
2,528 citations
TL;DR: A liquid culture system is described whereby proliferation of haemopoietic stem cells, production of granulocyte precursor cells (CFU‐C), and extensive granulopoiesis can be maintained in vitro for several months.
Abstract: A liquid culture system is described whereby proliferation of haemopoietic stem cells (CFU-S), production of granulocyte precursor cells (CFU-C), and extensive granulopoiesis can be maintained in vitro for several months. Such cultures consist of adherent and non-adherent populations of cells. The adherent population contains phagocytic mononuclear cells, “epithelial” cells, and “giant fat” cells. The latter appear to be particularly important for stem cell maintenance and furthermore there is a strong tendency for maturing granulocytes to selectively cluster in and around areas of “giant fat” cell aggregations. By “feeding” the cultures at weekly intervals, between 10 to 15 “population doublings” of functionally normal CFU-S regularly occurs. Increased “population doublings” may be obtained by feeding twice weekly. The cultures show initially extensive granulopoiesis followed, in a majority of cases, by an accumulation of blast cells. Eventually both blast cells and granulocytes decline and the cultures contain predominantly phagocytic mononuclear cells.
Culturing at 33°C leads to the development of a more profuse growth of adherent cells and these cultures show better maintenance of stem cells and increased cell density.
When tested for colony stimulating activity (CSA) the cultures were uniformly negative. Addition of exogenous CSA caused a rapid decline in stem cells, reduced granulopoiesis and an accumulation of phagocytic mononuclear cells.
2,178 citations
TL;DR: It is shown that the induced deletion of CXCR4, a receptor for CXC chemokine ligand (CXCL) 12 in adult mice, resulted in severe reduction of HSC numbers and increased sensitivity to myelotoxic injury, although it did not impair expansion of the more mature progenitors.
2,046 citations