Aberrant activation of the Wnt pathway is implicated in driving the formation of various human cancers, particularly those of the digestive tract. Inhibition of aberrant Wnt pathway activity in cancer cell lines efficiently blocks their growth, highlighting the great potential of therapeutics designed to achieve this in cancer patients. Here we provide an overview of the promise and pitfalls of current drug development strategies striving to inhibit the Wnt pathway and present new opportunities for therapeutic intervention.

Mining the Wnt pathway for cancer therapeutics

Background Surgical oncologists rely heavily on the histopathological assessment of surgical margins to ensure total excision of the tumor in patients with head and neck cancer. However, current techniques may not detect small numbers of cancer cells at the margins of resection or in cervical lymph nodes. Methods We used molecular techniques to determine whether clonal populations of infiltrating tumor cells harboring mutations of the p53 gene could be detected in histopathologically negative surgical margins and cervical lymph nodes of patients with squamous-cell carcinoma of the head and neck. Results We identified 25 patients with primary squamous-cell carcinoma of the head and neck containing a p53 mutation who appeared to have had complete tumor resection on the basis of a negative histopathological assessment. In 13 of these 25 patients, molecular analysis was positive for a p53 mutation in at least one tumor margin. In 5 of 13 patients with positive margins by this method (38 percent), the carcinom...

https://www.nejm.org/doi/pdf/10.1056/NEJM199502163320704

Molecular Assessment of Histopathological Staging in Squamous-Cell Carcinoma of the Head and Neck

The cross-regulation of Wnt/beta-catenin/Tcf ligands, kinases, and transcription factors with members of the nuclear receptor (NR) family has emerged as a clinically and developmentally important area of endocrine cell biology. Interactions between these signaling pathways result in a diverse array of cellular effects including altered cellular adhesion, tissue morphogenesis, and oncogenesis. Analyses of NR interactions with canonical Wnt signaling reveal two broad themes: Wnt/beta-catenin modulation of NRs (theme I), and ligand-dependent NR inhibition of the Wnt/beta-catenin/Tcf cascade (theme II). Beta-catenin, a promiscuous Wnt signaling member, has been studied intensively in relation to the androgen receptor (AR). Beta-catenin acts as a coactivator of AR transcription and is also involved in co-trafficking, increasing cell proliferation, and prostate pathogenesis. T cell factor, a transcriptional mediator of beta-catenin and AR, engages in a dynamic reciprocity of nuclear beta-catenin, p300/CREB binding protein, and transcriptional initiation factor 2/GC receptor-interaction protein, thereby facilitating hormone-dependent coactivation and transrepression. Beta-catenin responds in an equally dynamic manner with other NRs, including the retinoic acid (RA) receptor (RAR), vitamin D receptor (VDR), glucocorticoid receptor (GR), progesterone receptor, thyroid receptor (TR), estrogen receptor (ER), and peroxisome proliferator-activated receptor (PPAR). The NR ligands, vitamin D(3), trans/cis RA, glucocorticoids, and thiazolidines, induce dramatic changes in the physiology of cells harboring high Wnt/beta-catenin/Tcf activity. Wnt signaling regulates, directly or indirectly, developmental processes such as ductal branching and adipogenesis, two processes dependent on NR function. Beta-catenin has been intensively studied in colorectal cancer; however, it is now evident that beta-catenin may be important in cancers of the breast, prostate, and thyroid. This review will focus on the cross-regulation of AR and Wnt/beta-catenin/Tcf but will also consider the dynamic manner in which RAR/RXR, GR, TR, VDR, ER, and PPAR modulate canonical Wnt signaling. Although many commonalities exist by which NRs interact with the Wnt/beta-catenin signaling pathway, striking cell line and tissue-specific differences require deciphering and application to endocrine pathology.

Interaction of Nuclear Receptors with the Wnt/β-Catenin/Tcf Signaling Axis: Wnt You Like to Know?

CEA is a complex glycoprotein produced by 90% of colorectal cancers and contributes to the malignant characteristics of a tumor. It can be measured in serum quantitatively, and its level in plasma can be useful as a marker of disease. Because of its lack of sensitivity in the early stages of colorectal cancer, CEA measurement is an unsuitable modality for population screening. An elevated preoperative CEA is a poor prognostic sign and correlates with reduced overall survival after surgical resection of colorectal carcinoma. A failure of the CEA to return to normal levels after surgical resection is indicative of inadequate resection of occult systemic disease. Frequent monitoring of CEA postoperatively may allow identification of patients with metastatic disease for whom surgical resection or other localized therapy might be potentially beneficial. To identify this group, serial CEA measurement appears to be more effective than clinical evaluation or any other diagnostic modality, although its sensitivity for detecting recurrent disease is not as high for locoregional or pulmonary metastases as it is for liver metastases. Several studies have shown that a small percentage of patients followed postoperatively with CEA monitoring and who undergo CEA-directed salvage surgery for metastatic disease will be alive and disease-free 5 years after surgery. Furthermore, CEA levels after salvage surgery do appear to predict survival in patients undergoing resection of liver or pulmonary metastases. However, several authors argue that CEA surveillance is not cost-effective in terms of lives saved. In support of this argument, there is no clear difference in survival after resection of metastatic disease with curative intent between patients in whom the second-look surgery was performed on the basis of elevated CEA levels and those with other laboratory or imaging abnormalities. There is also no clear consensus on the frequency or duration of CEA monitoring, although the ASCO guidelines currently recommend every 2-3 months for at least 2 years after diagnosis. In the follow-up of patients undergoing palliative therapy, the CEA level correlates well with response, and CEA is indicative of not only response but may also identify patients with stable disease for whom there is also a demonstrated benefit in survival and symptom relief with combination chemotherapy. More recently, scintigraphic imaging after administration of radiolabeled antibodies afforded an important radionuclide technique that adds clinically significant information in assessing the extent and location of disease in patients with colorectal cancer above and beyond or complementary to conventional imaging modalities. Immunotherapy based on CEA is a rapidly advancing area of clinical research demonstrating antibody and T-cell responses.

Carcinoembryonic Antigen in the Staging and Follow-up of Patients with Colorectal Cancer

Objective: To determine whether an intensified follow-up of patients with colorectal cancer can lead to improved reresectability and a better long-term survival. Design: A prospective randomized trial of 106 patients. Setting: Oulu University Hospital, a referral center in northern Finland. Patients: A total of 106 consecutive patients who underwent radical resection for colorectal cancer, 54 of whom were randomized into a conventional follow-up group and 52 into an intensified follow-up group. Main Outcome Measures: After a 5-year follow-up, the time of detection of recurrence, the recurrence rates, the first method showing recurrence, the mode of recurrence, reresectability, and survival were compared between the groups. Results: The recurrences were identified earlier in the intensified follow-up group than in the conventional follow-up group (mean±SD, 10±5 months vs 15±10 months). The overall recurrence rate was 41%, with 39% in the conventional group and 42% in the intensified group. Carcinoembryonic antigen determination was the most common method showing recurrence in both groups. Endoscopy and ultrasound were beneficial in the intensified follow-up group, but computed tomography failed to improve the diagnostics. The mode of recurrence did not differ between the groups. Radical reresections were performed on 19% (8/43) of the patients, 14% (3/21) in the conventional group and 22% (5/22) in the intensified group. The cumulative 5-year survival was 54% in the conventional group and 59% in the intensified group. Conclusion: Earlier detection of recurrent colorectal cancer by intensified follow-up does not lead to either significantly increased reresectability or improved 5-year survival. (Arch Surg. 1995;130:1062-1067)

https://jamanetwork.com/HttpHandlers/ArticlePdfHandler.ashx?journal=SURG&articleId=596341&pdfFileName=archsurg_130_10_009.pdf

Five-year follow-up after radical surgery for colorectal cancer. Results of a prospective randomized trial.

Three hundred forty-one needle aspiration biopsies (NAB) of major salivary gland tumors were performed over a 32-year period. Eighty percent of tumors were benign, and 20% were malignant. Preoperative NAB findings were compared with pathologic diagnosis of the surgically resected specimen in all cases. Forty-six of 63 aspirates from malignant tumors were correctly diagnosed by NAB, establishing a sensitivity at 73%. Two hundred forty-nine of 265 aspirates from benign tumors were correctly diagnosed by NAB, establishing a specificity at 94%. Overall accuracy was 90%. Diagnostic error or difficulty in clinically localizing the tumor to the salivary gland was encountered in 64 patients with parotid tumors and 12 patients with submandibular tumors. NAB correctly localized over 85% of these tumors to the salivary gland, thus enabling both immediate and correct decision-making concerning subsequent management to be undertaken.

Needle aspiration biopsy of major salivary gland tumors. Its value.

Findings in our series of patients and a review of the literature seem to suggest that metastatic cancer to the thyroid is much more common that is clinically evident. The clinical presentation of an asymptomatic mass, normal thyroid functions, and a cold nodule on thyroid scan can occur months to years after treatment of a primary cancer and thus often produces a clinical dilemma. Workup should include ruling out other metastatic cancer and fine-needle aspiration of the thyroid mass. If isolated metastatic cancer to the thyroid is found, surgical resection should be performed, usually by lobectomy and isthmusectomy. Unfortunately, the prognosis is poor, but surgery often prolongs the disease-free interval and occasionally will be curative.

Clinical and pathologic correlations in disease metastatic to the thyroid gland

To assess monoclonal antibody (MAb) 17-1A and its F(ab')2 fragment in intraoperative radioimmunodetection and to evaluate further the clinical usefulness of a hand-held gamma-detecting probe (GDP), we injected radiolabeled monoclonal antibody 17-1A three to six days preoperatively or its F(ab')2 fragment two to three days preoperatively into 18 patients with colorectal cancer. Intraoperative GDP counts with tumor-tissue ratios of 1.5:1 or greater were obtained from 15 (75%) of 20 tumor sites, with ratios averaging 2.3:1 for fragments and 3.4:1 for whole antibody. The GDP counts contributed to intraoperative decision making in three patients, either by localization of tumor not identified by inspection or palpation or by mapping margins of resection with histologic confirmation of a local/regional recurrence. These preliminary data demonstrate that probe-directed, intraoperative radioimmunodetection can assist the surgeon in detecting subclinical tumor deposits and thus better evaluate the extent of primary or recurrent colorectal cancers intraoperatively.

Intraoperative probe-directed immunodetection using a monoclonal antibody.

Effect of 13-cis-retinoic acid on tumor prevention, tumor growth, and metastasis in experimental colon cancer

To examine the effect of the polar solvents on 1,2-dimethylhydrazine (DMH)-induced colon cancer, 100 male Sprague-Dawley rats were randomly allocated to a control and three treatment groups. Treated animals received N-methylformamide (NMF), dimethylsulfoxide (DMSO), or methylsulfonylmethane (MSM) added to drinking water 1 week before carcinogen injections commenced and for the duration of the experiment. Primary tumors were detected by serial laparotomy under ether anesthesia performed at 2-month intervals and commencing after carcinogen injections had been completed. The average time to tumor onset was significantly delayed in rats receiving NMF and MSM (P = 0.0141 and 0.0398 respectively, Mantel-Haenszel test). In addition, fewer poorly differentiated tumors were noted in treatment groups. No weight loss or toxicity was observed. These findings demonstrate that the polar solvents significantly reduce the latent period to tumor onset in DMH-induced colon cancer and indicate the need to further investigate such compounds as chemopreventive agents.

Daniel P. McCabe

Papers

Needle aspiration biopsy of major salivary gland tumors. Its value.

Clinical and pathologic correlations in disease metastatic to the thyroid gland

Intraoperative probe-directed immunodetection using a monoclonal antibody.

Effect of 13-cis-retinoic acid on tumor prevention, tumor growth, and metastasis in experimental colon cancer

Use of polar solvents in chemoprevention of 1,2-dimethylhydrazine-induced colon cancer