Author
Harold L. Moses
Other affiliations: Veterans Health Administration, Vanderbilt University Medical Center, New York University ...read more
Bio: Harold L. Moses is an academic researcher from Vanderbilt University. The author has contributed to research in topics: Transforming growth factor & Transforming growth factor beta. The author has an hindex of 114, co-authored 329 publications receiving 48503 citations. Previous affiliations of Harold L. Moses include Veterans Health Administration & Vanderbilt University Medical Center.
Papers published on a yearly basis
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TL;DR: It is revealed that fibroblasts have a more profound influence on the development and progression of carcinomas than was previously appreciated and this has important therapeutic implications.
Abstract: It is widely accepted that the development of carcinoma--the most common form of human cancer--is due to the accumulation of somatic mutations in epithelial cells. The behaviour of carcinomas is also influenced by the tumour microenvironment, which includes extracellular matrix, blood vasculature, inflammatory cells and fibroblasts. Recent studies reveal that fibroblasts have a more profound influence on the development and progression of carcinomas than was previously appreciated. These new findings have important therapeutic implications.
2,215 citations
TL;DR: Although myofibroblast-depleted tumors did not respond to gemcitabine, anti-CTLA4 immunotherapy reversed disease acceleration and prolonged animal survival, and underscores the need for caution in targeting carcinoma-associated fibroblasts in PDAC.
1,835 citations
TL;DR: TGF-β signaling in fibroblasts modulates the growth and oncogenic potential of adjacent epithelia in selected tissues and is associated with intraepithelial neoplasia in prostate and invasive squamous cell carcinoma of the forestomach.
Abstract: Stromal cells can have a significant impact on the carcinogenic process in adjacent epithelia. The role of transforming growth factor-beta (TGF-beta) signaling in such epithelial-mesenchymal interactions was determined by conditional inactivation of the TGF-beta type II receptor gene in mouse fibroblasts (Tgfbr2fspKO). The loss of TGF-beta responsiveness in fibroblasts resulted in intraepithelial neoplasia in prostate and invasive squamous cell carcinoma of the forestomach, both associated with an increased abundance of stromal cells. Activation of paracrine hepatocyte growth factor (HGF) signaling was identified as one possible mechanism for stimulation of epithelial proliferation. Thus, TGF-beta signaling in fibroblasts modulates the growth and oncogenic potential of adjacent epithelia in selected tissues.
1,332 citations
TL;DR: The complex nature of TGFβ signalling and crosstalk in the tumour microenvironment presents a unique challenge, and an opportunity to develop therapeutic intervention strategies for targeting cancer.
Abstract: Transforming growth factor-beta (TGFbeta) signalling regulates cancer through mechanisms that function either within the tumour cell itself or through host-tumour cell interactions. Studies of tumour-cell-autonomous TGFbeta effects show clearly that TGFbeta signalling has a mechanistic role in tumour suppression and tumour promotion. In addition, factors in the tumour microenvironment, such as fibroblasts, immune cells and the extracellular matrix, influence the ability of TGFbeta to promote or suppress carcinoma progression and metastasis. The complex nature of TGFbeta signalling and crosstalk in the tumour microenvironment presents a unique challenge, and an opportunity to develop therapeutic intervention strategies for targeting cancer.
1,270 citations
TL;DR: The data suggest that TGF-beta rapidly activates RhoA-dependent signaling pathways to induce stress fiber formation and mesenchymal characteristics.
Abstract: Transforming growth factor-beta1 (TGF-beta) can be tumor suppressive, but it can also enhance tumor progression by stimulating the complex process of epithelial-to-mesenchymal transdifferentiaion (EMT). The signaling pathway(s) that regulate EMT in response to TGF-beta are not well understood. We demonstrate the acquisition of a fibroblastoid morphology, increased N-cadherin expression, loss of junctional E-cadherin localization, and increased cellular motility as markers for TGF-beta-induced EMT. The expression of a dominant-negative Smad3 or the expression of Smad7 to levels that block growth inhibition and transcriptional responses to TGF-beta do not inhibit mesenchymal differentiation of mammary epithelial cells. In contrast, we show that TGF-beta rapidly activates RhoA in epithelial cells, and that blocking RhoA or its downstream target p160(ROCK), by the expression of dominant-negative mutants, inhibited TGF-beta-mediated EMT. The data suggest that TGF-beta rapidly activates RhoA-dependent signaling pathways to induce stress fiber formation and mesenchymal characteristics.
1,016 citations
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TL;DR: Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer.
51,099 citations
TL;DR: This work has been supported by the Department of the Army and the National Institutes of Health, and the author acknowledges the support and encouragement of the National Cancer Institute.
28,811 citations
TL;DR: The ability to control the expression of genes encoding these molecules and to target specific cell types provides opportunities to develop new diagnostic and therapeutic agents to induce the regression of the lesions and, possibly, to prevent their formation.
Abstract: Atherosclerosis, the principal cause of heart attack, stroke and gangrene of the extremities, is responsible for 50% of all mortality in the USA, Europe and Japan. The lesions result from an excessive, inflammatory-fibroproliferative response to various forms of insult to the endothelium and smooth muscle of the artery wall. A large number of growth factors, cytokines and vasoregulatory molecules participate in this process. Our ability to control the expression of genes encoding these molecules and to target specific cell types provides opportunities to develop new diagnostic and therapeutic agents to induce the regression of the lesions and, possibly, to prevent their formation.
10,861 citations
TL;DR: The molecular pathways of this cancer-related inflammation are now being unravelled, resulting in the identification of new target molecules that could lead to improved diagnosis and treatment.
Abstract: The mediators and cellular effectors of inflammation are important constituents of the local environment of tumours. In some types of cancer, inflammatory conditions are present before a malignant change occurs. Conversely, in other types of cancer, an oncogenic change induces an inflammatory microenvironment that promotes the development of tumours. Regardless of its origin, 'smouldering' inflammation in the tumour microenvironment has many tumour-promoting effects. It aids in the proliferation and survival of malignant cells, promotes angiogenesis and metastasis, subverts adaptive immune responses, and alters responses to hormones and chemotherapeutic agents. The molecular pathways of this cancer-related inflammation are now being unravelled, resulting in the identification of new target molecules that could lead to improved diagnosis and treatment.
9,282 citations
TL;DR: The principal mechanisms that govern the effects of inflammation and immunity on tumor development are outlined and attractive new targets for cancer therapy and prevention are discussed.
8,664 citations