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Cancer Research Landmarks

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.

Read the commentary by Mu and colleagues

Read the article by van Griethuysen and colleagues

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.

Read the commentary by Ho and Jaffee

Read the article by Zhu and colleagues

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.

Read the commentary by Krastev and colleagues

Read the article by Murai and colleagues

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.

Read the commentary by Fang and Kang

Read the article by Onder and colleagues

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.

Read the commentary by Bergholz and Zhao

Read the article by O'Reilly and colleagues

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.

Read the commentary by Gabrilovich

Read the article by Rodriguez and colleagues

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.

Read the commentary by Augustin and Koh

Read the article by Tong and colleagues

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.

Read the commentary by Lai and colleagues

Read the article by Blank and colleagues

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.

Read the commentary by Hanrahan and Solit

Read the article by Brose and colleagues

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.

Read the commentary by Linette and Carreno

Read the article by Banchereau and colleagues

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.

Read the commentary by Clark and Molloy

Read the article by Esteller and colleagues

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.

Read the commentary by Kim and Simon

Read the article by Zhong and colleagues

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.

Read the commentary by Cukierman

Read the article by Olumi and colleagues

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.

Read the commentary by Issa

Read the article by Kane and colleagues

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.

Read the commentary by Napoli and colleagues

Read the article by Baker and colleagues

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.

Read the commentary by Puleo and Polyak

Read the article by Soule and colleagues

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.

Read the commentary by Joosse and Klaus

Read the article by Leon and colleagues

Submit your Landmark Study to Cancer Research

Cancer Research invites the submission of impactful basic and translational research providing biological, clinical, and population-level insights that advance the understanding and treatment of cancer.

Submit your article here

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