In recognition of the 50th anniversary of the National Cancer Act, we are pleased to present the Cancer Research Landmarks series.
The National Cancer Act launched a national commitment to advancing our understanding of cancer biology to make progress in treating and preventing this devastating collection of diseases. The groundbreaking legislation galvanized the cancer research community to make discoveries that have culminated in tangibly improved outcomes for many cancer patients.
The Landmarks series highlights pivotal NCI-funded basic, translational, and clinical studies published in Cancer Research over the last fifty years with commentaries reflecting on how these discoveries impacted the trajectory of the field.
Computational Radiomics System to Decode the Radiographic Phenotype
An open-source platform was developed that enabled processing and extraction of radiomic features and established a reference standard for radiomic analyses, promoting reproducible science within the quantitative imaging field to better address the needs of cancer research and clinical oncology.
CSF1/CSF1R Blockade Reprograms Tumor-Infiltrating Macrophages and Improves Response to T-cell Checkpoint Immunotherapy in Pancreatic Cancer Models
Macrophage reprogramming by inhibition of CSF1R signaling was found to enhance the efficacy of T cell checkpoint immunotherapy in pancreatic cancer, highlighting the potential of targeting myeloid cells to alleviate the immunosuppressive tumor microenvironment and improve the response to immune checkpoint inhibitors.
Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors
In addition to inhibiting PARP enzymatic activity, PARP inhibitors lock PARP onto DNA at sites of damage and exert cytotoxic effects through formation of protein aggregates on DNA. This discovery provided important mechanistic insights into this widely used class of cancer therapeutics.
Loss of E-Cadherin Promotes Metastasis via Multiple Downstream Transcriptional Pathways
The finding that E-cadherin loss in cancer cells promotes a mesenchymal cell state and metastatic phenotype by both disrupting cell-cell contacts and altering intracellular signaling established E-cadherin as an important regulator, rather than just a marker, of the epithelial-mesenchymal transition.
mTOR Inhibition Induces Upstream Receptor Tyrosine Kinase Signaling and Activates Akt
The finding that mTOR inhibition induces feedback activation of Akt provided insights into pathway crosstalk and reciprocal resistance mechanisms, highlighting that rational combination therapies targeting multiple components of signaling networks can enhance cancer treatment efficacy.
Blockade of B7-H1 and PD-1 by Monoclonal Antibodies Potentiates Cancer Therapeutic Immunity
The findings that tumor cell PD-L1 mediates T cell evasion and that targeting PD-L1 promotes anti-tumor immunity contributed to the preclinical rationale for the development of immune checkpoint blockade therapies.
Arginase I Production in the Tumor Microenvironment by Mature Myeloid Cells Inhibits T-Cell Receptor Expression and Antigen-Specific T-Cell Responses
The search for regulators of immune responses in cancer led to the identification of arginase I-producing myeloid cells, which later became known as myeloid-derived suppressor cells, as central mediators of tumor immune evasion.
Akt Stimulates Aerobic Glycolysis in Cancer Cells
The finding that constitutive activation of AKT increases aerobic glycolysis and renders cancer cells dependent on glucose provided an early connection between a specific oncogene and altered cancer metabolism.
Vascular Normalization by Vascular Endothelial Growth Factor Receptor 2 Blockade Induces a Pressure Gradient Across the Vasculature and Improves Drug Penetration in Tumors
This study uncovered that normalizing the vasculature within a tumor by blocking VEGF signaling improved drug delivery in solid tumors and prompted research to use anti-angiogenic agents in combination therapy regimens.
PD-L1/B7H-1 Inhibits the Effector Phase of Tumor Rejection by T Cell Receptor (TCR) Transgenic CD8+ T Cells
This study identified the ability of PD-1/PD-L1 engagement to trigger inhibitory signals during the effector phase of the CD8+ T cell response and demonstrated that targeting this interaction can enhance the anti-tumor activity of adoptively transferred T cells. These findings supported research into immune checkpoint blockade and genetic engineering in T cell therapy approaches for treating cancer.
BRAF and RAS Mutations in Human Lung Cancer and Melanoma
The identification of differences in BRAF mutation frequency and allele distribution in melanoma and lung cancer indicated that not all BRAF mutations are functionally equivalent across cancer types. This finding helped lay the groundwork for subsequent research elucidating biochemical differences between mutant alleles within the same gene and the impact of cancer lineage on drug sensitivity.
Immune and Clinical Responses in Patients with Metastatic Melanoma to CD34+ Progenitor-derived Dendritic Cell Vaccine
The clinical trial indicating that CD34+ progenitor-derived dendritic cells pulsed with melanoma antigens safely induce anti-tumor immunity in patients with metastatic melanoma contributed to the clinical development of dendritic cell vaccines alone and in combination with other immunotherapies.
A Gene Hypermethylation Profile of Human Cancer
A pan-cancer analysis of DNA promoter methylation in genes that are known drivers of tumorigenesis revealed that oncogene hypermethylation was a feature of each of the tumor types studied and cancer type could be identified based on the unique methylation patterns, indicating the pervasiveness and spectrum of epigenetic alterations in cancer.
Overexpression of Hypoxia-inducible Factor 1α in Common Human Cancers and Their Metastases
This paper reported overexpression of HIF-1α across a broad spectrum of human tumors that correlated with increased tumor cell proliferation, metastasis, and angiogenesis. This initial clinical data helped identify the role of HIF-1α in human cancer progression and spurred further investigation into how cancer cells adapt to and influence the microenvironment.
Carcinoma-associated Fibroblasts Direct Tumor Progression of Initiated Human Prostatic Epithelium
This study shows that fibroblasts associated with carcinomas stimulate tumor progression of initiated non-tumorigenic epithelial cells, revealing that carcinogenesis involves alterations in the epithelium as well as contributions from the surrounding supportive stromal tissue.
Methylation of the hMLH1 Promoter Correlates with Lack of Expression of hMLH1 in Sporadic Colon Tumors and Mismatch Repair-defective Human Tumor Cell Lines
This work described methylation in the promoter region of the DNA mismatch repair gene MLH1 that corresponded with loss of MLH1 expression in colon cancer, identifying an epigenetic mechanism by which tumor cells can perturb mismatch repair genes and inactivate DNA repair pathways.
p53 Gene Mutations Occur in Combination with 17p Allelic Deletions as Late Events in Colorectal Tumorigenesis
A sequencing study identified loss of one TP53 allele and mutation of the other during the transition from adenoma to carcinoma in the colon. This finding advanced the understanding of genetic alterations responsible for multistep tumorigenesis and prompted further research into mutant p53 gain-of-function and the causal role of p53 defects in tumor progression.
Isolation and Characterization of a Spontaneously Immortalized Human Breast Epithelial Cell Line, MCF-10
Establishment of the MCF-10 cell lines provided a valuable resource to the breast cancer research community, allowing researchers to model key aspects of normal breast epithelial biology and malignant progression.
Smoking and Drinking in Relation to Oral and Pharyngeal Cancer
An early population-level study implicated smoking and alcohol consumption as independent risk factors responsible for nearly 75% of all oral and pharyngeal cancers and indicated that quitting smoking could greatly reduce the risk of carcinogenesis.
LNCaP Model of Human Prostatic Carcinoma
The LNCaP cell line was isolated from a human prostate tumor and provided a malignant and hormone-responsive cell line model that maintains many key features of the disease. The LNCaP model has been used extensively in investigations to provide insights into prostate cancer biology.
Photoradiation Therapy for the Treatment of Malignant Tumors
The clinical investigation demonstrating the efficacy of photoradiation therapy using hematoporphyrin derivative and red light for treating a wide range of recurrent solid tumors in patients helped establish photodynamic therapy as a strategy for cancer treatment.
Estrogen Receptor as an Independent Prognostic Factor for Early Recurrence in Breast Cancer
Identification of a connection between loss of the estrogen receptor and disease aggression was an early step in the classification of breast cancer subtypes that have guided the clinical management of patients.
Free DNA in the Serum of Cancer Patients and the Effect of Therapy
This early investigation evaluated the presence of circulating DNA in cancer patients and healthy individuals, reporting that high serum DNA concentrations correlate with metastatic disease and poor response to treatment. The study helped to establish the potential for using liquid biopsies in diagnosing cancer and monitoring response to therapy.
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