Correspondence

The Chromogranin–Secretogranin Family

N Engl J Med 2003; 348:2579-2580June 19, 2003

Article

To the Editor:

Taupenot et al. (March 20 issue)1 state in their review article that the prognostic value of chromogranin A immunoreactivity in colorectal cancer has not been established. In fact, four out of five studies identify extensive neuroendocrine differentiation as an independent prognostic factor in Dukes' stage C colorectal cancer.2-4 Neuroendocrine differentiation also predicts a more aggressive clinical course in undifferentiated small-cell colorectal cancer.5

Hans Scherübl, M.D.
Patricia Grabowski, M.D.
Benjamin Franklin University Hospital, D-12200 Berlin, Germany
hans.scheruebl@medizin.fu-berlin.de

5 References

1. 1

   Taupenot L, Harper KL, O'Connor DT. The chromogranin-secretogranin family. N Engl J Med 2003;348:1134-1149
   Full Text | Web of Science | Medline

2. 2

   Hamada Y, Oishi A, Shoji T, et al. Endocrine cells and prognosis in patients with colorectal carcinoma. Cancer 1992;69:2641-2646
   CrossRef | Web of Science | Medline

3. 3

   de Bruine AP, Wiggers T, Beek C, et al. Endocrine cells in colorectal adenocarcinomas: incidence, hormone profile and prognostic relevance. Int J Cancer 1993;54:765-771
   CrossRef | Web of Science | Medline

4. 4

   Grabowski P, Schindler I, Anagnostopoulos I, et al. Neuroendocrine differentiation is a relevant prognostic factor in stage III-IV colorectal cancer. Eur J Gastroenterol Hepatol 2001;13:405-411
   CrossRef | Web of Science | Medline

5. 5

   Grabowski P, Schonfelder J, Ahnert-Hilger G, et al. Expression of neuroendocrine markers: a signature of human undifferentiated carcinoma of the colon and rectum. Virchows Arch 2002;441:256-263
   CrossRef | Web of Science | Medline

To the Editor:

Taupenot et al. mention the accumulation of chromogranin A in the preamyloid plaques of Alzheimer's disease and its activation of brain microglial cells, leading to neuronal degeneration. Chromogranin A has been shown to trigger the generation of nitric oxide in brain microglial cells.1 These observations are important in the context of the recent angiogenesis hypothesis with respect to Alzheimer's disease,2 which proposes a central role of vascular endothelial cells in the destruction of cortical neurons. Angiogenesis is presumed to be induced by vasoactive mediators such as nitric oxide, hypoxia-inducible factor 1α, and vascular endothelial growth factor, particularly if the gene expression of an endogenous inhibitor of angiogenesis, thrombospondin, is reduced near focal lesions of Alzheimer's disease.2,3 I wonder whether the accumulation of chromogranin A in senile plaques and the generation of nitric oxide have an important role in the angiogenic injury to neuronal cells that has been proposed as part of this new hypothesis. If this is the case, further studies of chromogranin A in Alzheimer's disease may yield insights into the proposed angiogenic origin of Alzheimer's disease.

Jacob C. Tony, M.D.
Midstaffordshire General Hospital, Stafford ST16 3SA, United Kingdom
tjacob33@hotmail.com

3 References

1. 1

   Taupenot L, Ciesielski-Treska J, Ulrich G, Chasserot-Golaz S, Aunis D, Bader MF. Chromogranin A triggers a phenotypic transformation and the generation of nitric oxide in brain microglial cells. Neuroscience 1996;72:377-389
   CrossRef | Web of Science | Medline

2. 2

   Vagnucci AH Jr, Li WW. Alzheimer's disease and angiogenesis. Lancet 2003;361:605-608
   CrossRef | Web of Science | Medline

3. 3

   Buee L, Hof PR, Roberts DD, Delacourte A, Morrison JH, Fillit HM. Immunohistochemical identification of thrombospondin in normal human brain and in Alzheimer's disease. Am J Pathol 1992;141:783-788
   Web of Science | Medline

Author/Editor Response

Scherübl and Grabowski call our attention to recent reports that profiling of the degree of neuroendocrine differentiation of cells in colorectal cancer (adenocarcinoma) with the use of the neuroendocrine markers chromogranin A and synaptophysin may yield prognostic information about the course of such tumors: increasing numbers of neuroendocrine cells in such tumors portend shorter patient survival.1 It is intriguing that the occurrence of such neuroendocrine cells as only a small percentage of the total cells (1 to 2 percent) may alter the prognosis substantially.

Thus, chromogranin A expression may portend a poor prognosis in neoplasms that typically have little or no such neuroendocrine character, as has already been established for prostate cancer.2 Whether chromogranin A itself (or its biologically active fragments) alters the behavior of such neoplasms is not clear.

Tony advances the novel and intriguing hypothesis that endothelial-cell angiogenesis might provide a link between chromogranin A expression in senile plaques in Alzheimer's disease3 and progression of Alzheimer's disease, as follows: chromogranin A leads to microglial activation with nitric oxide formation,3 which leads to nitric oxide–induced angiogenesis,4 which leads to the accumulation of β-amyloid (or other neurotoxins) in areas of capillary proliferation,2,5 resulting in local neuronal injury. This scheme might provide a new and fruitful line of investigation into the pathophysiology of neurodegenerative diseases.

Laurent J.C. Taupenot, Ph.D.
Kimberly L. Harper, M.D.
Daniel T. O'Connor, M.D.
University of California, San Diego, San Diego, CA 92161
doconnor@ucsd.edu

5 References

1. 1

   Grabowski P, Schindler I, Anagnostopoulos I, et al. Neuroendocrine differentiation is a relevant prognostic factor in stage III-IV colorectal cancer. Eur J Gastroenterol Hepatol 2001;13:405-411
   CrossRef | Web of Science | Medline

2. 2

   Morbidelli L, Donnini S, Ziche M. Role of nitric oxide in the modulation of angiogenesis. Curr Pharm Des 2003;9:521-530
   CrossRef | Web of Science | Medline

3. 3

   Munoz DG. Chromogranin A-like immunoreactive neurites are major constituents of senile plaques. Lab Invest 1991;64:826-832
   Web of Science | Medline

4. 4

   Taupenot L, Ciesielski-Treska J, Ulrich G, Chasserot-Golaz S, Aunis D, Bader MF. Chromogranin A triggers a phenotypic transformation and the generation of nitric oxide in brain microglial cells. Neuroscience 1996;72:377-389
   CrossRef | Web of Science | Medline

5. 5

   Vagnucci AH Jr, Li WW. Alzheimer's disease and angiogenesis. Lancet 2003;361:605-608
   CrossRef | Web of Science | Medline

Citing Articles (1)

Citing Articles

1. 1

   Alexander W. Jahng, Solomon S. Liao. (2006) Successful Palliation with Octreotide of a Neuroendocrine Syndrome from Malignant Melanoma. Journal of Pain and Symptom Management 32:2, 191-195
   CrossRef